KR20220127513A - Prostate cancer subtype classification method and classification apparatus - Google Patents
Prostate cancer subtype classification method and classification apparatus Download PDFInfo
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- KR20220127513A KR20220127513A KR1020210031879A KR20210031879A KR20220127513A KR 20220127513 A KR20220127513 A KR 20220127513A KR 1020210031879 A KR1020210031879 A KR 1020210031879A KR 20210031879 A KR20210031879 A KR 20210031879A KR 20220127513 A KR20220127513 A KR 20220127513A
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Abstract
Description
본 발명은 전립선암의 보다 효과적인 치료 방법을 선택하거나, 예후 예측을 위하여 전립선암의 아형을 분류하는 방법 및 분류하는 장치에 관한 것이다.The present invention relates to a method and apparatus for classifying prostate cancer subtypes in order to select a more effective treatment method for prostate cancer or to predict a prognosis.
전립선암은 전세계 남성 암 중 가장 흔히 발병하는 암이며 사망률 2위를 차지한다. 50세 이상 남성에게 발병하며 나이가 들수록 급격하게 환자수가 증가하는 특징이 있다. 보통은 서서히 진행하지만, 악성으로 발전하여 전이가 일어나면 치료가 극히 어려운 질환이다. 전이는 주로 전립선암 주위의 림프절, 골반뼈, 척추뼈와 방광으로 시작하여 점차 전신에 퍼지게 된다.Prostate cancer is the most common cancer in men worldwide and the second leading cause of death. It occurs in men over the age of 50, and the number of patients rapidly increases with age. It usually progresses slowly, but when it develops into malignancy and metastasizes, it is extremely difficult to treat. Metastasis begins mainly in the lymph nodes, pelvic bones, vertebrae, and bladder around the prostate cancer and gradually spreads throughout the body.
현재 전립선암 진단 방법에는 전립선특이항원 검사법 (PSA test), 직장수지검사 등이 일차적으로 사용되고, 경직장초음파, CT, MRI, WBBS (Whole body bone scan)의 영상 진료법이 있으며, 조직검사도 시행되고 있다. 하지만, 대부분의 경우 진단 정확도가 낮고, 초기 진단이 어려우며, 전이 여부를 파악하기 힘든 방법으로 전립선비대증 및 전립선염과 같은 양성 질환과의 구분도 명확하지 않은 단점이 있어, 진단이 쉽지 않다.Currently, prostate cancer diagnosis methods include prostate-specific antigen test (PSA test) and digital rectal examination. have. However, in most cases, diagnostic accuracy is low, initial diagnosis is difficult, and it is difficult to determine whether or not metastasis is present.
한편, 약물유전체학(Pharmacogenomics)은 약물 치료에 대한 대상체의 반응에 영향을 미치는 유전되는 특성에 관한 연구이다. 약물 치료에 대한 차별적인 반응은 약물 대사에 영향을 미치는 근원적인 유전적 다형성이나 때때로 돌연변이라고 불리는 유전적인 변이가 원인일 수도 있다. 이러한 유전적 다형성에 대한 분류는 해로운 약물 반응성을 예방하고 적합한 약물 투여 요법을 용이하게 하는데 도움이 될 수도 있다.On the other hand, pharmacogenomics (Pharmacogenomics) is a study on inherited characteristics that affect the response of a subject to drug treatment. Differential responses to drug treatment may be due to underlying genetic polymorphisms that affect drug metabolism or genetic variations, sometimes called mutations. Classification of these genetic polymorphisms may help prevent detrimental drug reactivity and facilitate appropriate drug dosing regimens.
임상 환경에서, 약물유전체학은 의사가 각각의 환자에 대하여 적절한 약제 및 이들 약제의 적절한 투여량을 선택하는 것을 가능하게 할 수도 있어. 이는 암과 같이 치료 반응성이나 예후 예측에 대한 광범위한 이질성을 갖는 질병에서 중요하다. 특히, 전립선암 치료를 위하여 안드로겐 억제제, 도세탁셀, 방사선 치료 등의 치료 방식이나 순서를 선택하기 위하여, 전립선암의 아형에 따른 분류가 필요한 실정이다.In a clinical setting, pharmacogenomics may enable a physician to select appropriate medications and appropriate dosages of these agents for each patient. This is important in diseases with widespread heterogeneity in treatment responsiveness or prognosis, such as cancer. In particular, in order to select a treatment method or sequence of androgen inhibitors, docetaxel, radiation therapy, etc. for the treatment of prostate cancer, classification according to the subtype of prostate cancer is required.
본 발명의 일 목적은 암, 특히는 전립선암의 아형을 분류하는 방법을 제공하고자 한다. One object of the present invention is to provide a method for classifying subtypes of cancer, particularly prostate cancer.
본 발명의 다른 목적은 암, 특히는 전립선암의 아형을 분류하기 위한 장치를 제공하고자 한다.Another object of the present invention is to provide a device for classifying subtypes of cancer, in particular prostate cancer.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당 업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical task to be achieved by the present invention is not limited to the tasks mentioned above, and other tasks not mentioned will be clearly understood by those of ordinary skill in the art from the following description.
이하, 본원에 기재된 다양한 구체예가 도면을 참조로 기재된다. 하기 설명에서, 본 발명의 완전한 이해를 위해서, 다양한 특이적 상세 사항, 예컨대, 특이적 형태, 조성물 및 공정 등이 기재되어 있다. 그러나, 특정의 구체예는 이들 특이적 상세 사항 중 하나 이상 없이, 또는 다른 공지된 방법 및 형태와 함께 실행될 수 있다. 다른 예에서, 공지된 공정 및 제조 기술은 본 발명을 불필요하게 모호하게 하지 않게 하기 위해서, 특정의 상세사항으로 기재되지 않는다. "한 가지 구체예" 또는 "구체예"에 대한 본 명세서 전체를 통한 참조는 구체예와 결부되어 기재된 특별한 특징, 형태, 조성 또는 특성이 본 발명의 하나 이상의 구체예에 포함됨을 의미한다. 따라서, 본 명세서 전체에 걸친 다양한 위치에서 표현된 "한 가지 구체예에서" 또는 "구체예"의 상황은 반드시 본 발명의 동일한 구체예를 나타내지는 않는다. 추가로, 특별한 특징, 형태, 조성, 또는 특성은 하나 이상의 구체예에서 어떠한 적합한 방법으로 조합될 수 있다.BRIEF DESCRIPTION OF THE DRAWINGS Various embodiments described herein are described below with reference to the drawings. In the following description, various specific details are set forth, such as specific forms, compositions and processes, and the like, for a thorough understanding of the present invention. However, certain embodiments may be practiced without one or more of these specific details, or in conjunction with other known methods and forms. In other instances, well-known processes and manufacturing techniques have not been described in specific detail in order not to unnecessarily obscure the present invention. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, form, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Thus, references to "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Additionally, the particular features, forms, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.
본 발명 내 특별한 정의가 없으면 본 명세서에 사용된 모든 과학적 및 기술적인 용어는 본 발명이 속하는 기술분야에서 당 업자에 의하여 통상적으로 이해되는 것과 동일한 의미를 가진다.Unless otherwise defined in the present invention, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
본 발명의 일 구현 예에 따르면, 목적하는 개체에서 발병하였거나 발병 가능성이 높은 전립선암을 루미널 A(luminal A) 아형, 루미널 S(luminal S) 아형, 면역 침윤성/혈관형성을 띄는 공격적인 변이형 전립선암(aggressive variant PCs immune-infiltrative/angiogenic; AVPC-I) 아형 및 MYC 활성을 띄는 공격적인 변이형 전립선암(aggressive variant PCs Myc active; AVPC-M) 아형으로 분류하는 단계를 포함하는, 전립선암의 아형 분류 방법에 관한 것이다. According to one embodiment of the present invention, prostate cancer that has occurred or is highly likely to develop in a subject of interest is classified as a luminal A subtype, a luminal S subtype, or an aggressive variant with immune invasiveness/angiogenesis. Prostate cancer (aggressive variant PCs immune-infiltrative/angiogenic; AVPC-I) subtype and MYC activity of the aggressive variant PCs Myc active; It relates to a subtype classification method.
본 발명에서, 상기 아형 분류 시 상기 목적하는 개체의 생물학적 시료에서 SPOP, PRDM1, ETS, PTEN, TP53, PIK3CA, PTK2 및 RB1 유전자로 이루어진 군에서 선택되는 적어도 하나의 유전자에서 돌연변이 여부를 검출하여 수행될 수 있으나, 이에 제한되는 것은 아니다. In the present invention, when classifying the subtype, at least one gene selected from the group consisting of SPOP, PRDM1, ETS, PTEN, TP53, PIK3CA, PTK2 and RB1 genes in the biological sample of the target individual is mutated to be performed by detecting whether However, the present invention is not limited thereto.
본 발명에서 상기 "목적하는 개체"란, 전립선암이 발병하였거나 발병 가능성이 높은 개체로서, 본 발명의 목적 상 상기 개체는 전립선암 환자일 수 있으며, 포유동물 및 비-포유동물을 모두 포함할 수 있다. 여기서, 상기 포유동물의 예로는 인간, 비-인간 영장류, 예컨대 침팬지, 다른 유인원 또는 원숭이 종; 축산 동물, 예컨대 소, 말, 양, 염소, 돼지; 사육 동물, 예컨대 토끼, 개 또는 고양이; 실험 동물, 예를 들어 설치류, 예컨대 래트, 마우스 또는 기니아 피그 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. 또한, 본 발명에서 상기 비-포유동물의 예로는 조류 또는 어류 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the "target subject" refers to an individual who has or is highly likely to develop prostate cancer. For the purpose of the present invention, the subject may be a prostate cancer patient, and may include both mammals and non-mammals. have. Here, examples of such mammals include humans, non-human primates such as chimpanzees, other apes or monkey species; livestock animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs or cats; laboratory animals such as rodents such as rats, mice or guinea pigs, but are not limited thereto. In addition, examples of the non-mammal in the present invention may include, but are not limited to, birds or fish.
본 발명에서 상기 "생물학적 시료"는 개체로부터 얻어지거나 개체로부터 유래된 임의의 물질, 생물학적 체액, 조직 또는 세포를 의미하는 것으로, 예를 들면, 전혈(whole blood), 백혈구(leukocytes), 말초혈액 단핵 세포(peripheral blood mononuclear cells), 백혈구 연층(buffy coat), 혈장(plasma), 혈청(serum), 객담(sputum), 눈물(tears), 점액(mucus), 세비액(nasal washes), 비강 흡인물(nasal aspirate), 호흡(breath), 소변(urine), 정액(semen), 침(saliva), 복강 세척액(peritoneal washings), 복수(ascites), 낭종액(cystic fluid), 뇌척수막 액(meningeal fluid), 양수(amniotic fluid), 선액(glandular fluid), 췌장액(pancreatic fluid), 림프액(lymph fluid), 흉수(pleural fluid), 유두 흡인물(nipple aspirate), 기관지 흡인물(bronchial aspirate), 활액(synovial fluid), 관절 흡인물(joint aspirate), 기관 분비물(organ secretions), 세포(cell), 세포 추출물(cell extract) 또는 뇌척수액(cerebrospinal fluid)을 포함할 수 있지만, 바람직하게는 전립선암 조직 또는 그 유래 세포일 수 있다.In the present invention, the "biological sample" refers to any material, biological fluid, tissue or cell obtained from or derived from an individual, for example, whole blood, leukocytes, peripheral blood mononuclear peripheral blood mononuclear cells, buffy coat, plasma, serum, sputum, tears, mucus, nasal washes, nasal aspirate (nasal aspirate), breath, urine, semen, saliva, peritoneal washings, ascites, cystic fluid, meningeal fluid , amniotic fluid, glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple aspirate, bronchial aspirate, synovial fluid), joint aspirate, organ secretions, cells, cell extract, or cerebrospinal fluid, but preferably prostate cancer tissue or its derivative It may be a cell.
본 발명에서, 상기 SPOP 유전자는 반점형 POZ 단백질(Speckle-type POZ 단백질)을 코딩하는 유전자이고, 상기 반점형 POZ 단백질은 상기 히스톤 디아세틸라제, 코어 히스톤 및 기타 히스톤 관련 단백질과 상호 작용하는 사멸 관련 단백질 6의 전사 억제 활성을 조절할 수 있는 단백이다. 여기서, 상기 반점형 POZ 단백질은 서열번호 1의 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the SPOP gene is a gene encoding a speckle-type POZ protein, and the speckle-type POZ protein is apoptosis-related interacting with the histone deacetylase, core histones and other histone-related proteins. It is a protein that can regulate the transcriptional repression activity of
본 발명에서, 상기 PRDM1 유전자는 PR 영역 아연 핑거 단백질 1(BLIMP-1)을 코딩하고 6번 염색체 상의 유전자이다. 여기서, 상기 PR 영역 아연 핑거 단백질 1은 서열번호 2의 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the PRDM1 gene encodes a PR region zinc finger protein 1 (BLIMP-1) and is a gene on
본 발명에서, 상기 ETS 유전자 패밀리는 아미노산 영역에서 유사성을 나타내는 전사인자 패밀리로, 하기 표 1에 나타낸 12개의 서브 패밀리로 구분될 수 있으나, 본 발명에서는 상기 ETS 유전자는 ERG, ETV1, ETV4, ETV5 및 ETV6으로 이루어진 군에서 선택된 1종 이상의 유전자일 수 있으나, 이에 제한되지는 않는다.In the present invention, the ETS gene family is a transcription factor family showing similarity in the amino acid region, and can be divided into 12 sub-families shown in Table 1 below. In the present invention, the ETS gene is ERG, ETV1, ETV4, ETV5 and It may be one or more genes selected from the group consisting of ETV6, but is not limited thereto.
본 발명에서, 상기 ERG 유전자는 ETS 전사인자 패밀리를 구성하는 유전자로, 배아발달, 세포 증식, 세포 분화, 혈관 신생, 염증 및 세포 자멸사를 조절하는 ERG 전사인자 단백질을 코딩하는 유전자이다. 여기서, 상기 ERG 전사인자 단백질은 서열번호 3의 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the ERG gene is a gene constituting the ETS transcription factor family, and is a gene encoding an ERG transcription factor protein that regulates embryonic development, cell proliferation, cell differentiation, angiogenesis, inflammation, and apoptosis. Here, the ERG transcription factor protein may consist of the amino acid sequence of SEQ ID NO: 3, but is not limited thereto.
본 발명에서, 상기 ETV1 유전자는 ETS 전사인자 패밀리를 구성하는 유전자로, 배아발달, 세포 증식, 세포 분화, 혈관 신생, 염증 및 세포 자멸사를 조절하는 ETV1 전위변형 단백질을 코딩하는 유전자이다. 여기서, 상기 ETV1 전위변형 단백질은 서열번호 4의 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the ETV1 gene is a gene constituting the ETS transcription factor family, and is a gene encoding an ETV1 translocation protein that regulates embryonic development, cell proliferation, cell differentiation, angiogenesis, inflammation and apoptosis. Here, the ETV1 translocation protein may be composed of the amino acid sequence of SEQ ID NO: 4, but is not limited thereto.
본 발명에서, 상기 ETV4 유전자는 ETS 전사인자 패밀리를 구성하는 유전자로, 유잉 육종 및 골외 유잉 육종과 관련되는 ETV4 전위변형 단백질을 코딩하는 유전자이다. 여기서, 상기 ETV4 전위변형 단백질은 서열번호 5의 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the ETV4 gene is a gene constituting the ETS transcription factor family and encodes an ETV4 translocation protein associated with Ewing's sarcoma and extraosseous Ewing's sarcoma. Here, the ETV4 translocation protein may be composed of the amino acid sequence of SEQ ID NO: 5, but is not limited thereto.
본 발명에서, 상기 ETV5 유전자는 ETS 전사인자 패밀리를 구성하는 유전자로, 세르톨리 세포에서 발현되어 정자생성에 중요한 역할을 하는 ETV5 전위변형 단백질을 코딩하는 유전자이다. 여기서, 상기 ETV5 전위변형 단백질은 서열번호 6의 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the ETV5 gene is a gene constituting the ETS transcription factor family, and is a gene encoding an ETV5 translocation protein that is expressed in Sertoli cells and plays an important role in spermatogenesis. Here, the ETV5 translocation protein may be composed of the amino acid sequence of SEQ ID NO: 6, but is not limited thereto.
본 발명에서, 상기 ETV6 유전자는 ETS 전사인자 패밀리를 구성하는 유전자로, 혈액 조직의 발달과 성장을 조절하는 다양한 세포를 조절하는 ETV6 전위변형 단백질을 코딩하는 유전자이다. 여기서, 상기 ETV6 전위변형 단백질은 서열번호 7 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the ETV6 gene is a gene constituting the ETS transcription factor family, and is a gene encoding an ETV6 translocation protein that regulates various cells that control the development and growth of blood tissues. Here, the ETV6 translocation protein may be composed of the amino acid sequence of SEQ ID NO: 7, but is not limited thereto.
본 발명에서, 상기 PTEN 유전자는 포스파타제 및 텐신 동족체(Phosphatase and tensin homolog; PTEN) 단백질을 코딩하는 유전자로, 상기 유전자의 돌연변이는 암과 관련되어 있다고 알려져 있다. 여기서, 상기 PTEN 단백질은 서열번호 8의 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the PTEN gene is a gene encoding a phosphatase and tensin homolog (PTEN) protein, and mutation of the gene is known to be associated with cancer. Here, the PTEN protein may consist of the amino acid sequence of SEQ ID NO: 8, but is not limited thereto.
본 발명에서, 상기 TP53 유전자는 p53 단백질을 코딩하는 유전자이다. 여기서, 상기 p53 단백질은 서열번호 9의 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the TP53 gene is a gene encoding a p53 protein. Here, the p53 protein may consist of the amino acid sequence of SEQ ID NO: 9, but is not limited thereto.
본 발명에서, 상기 PIK3CA 유전자는 ATP를 사용하여 PtdIns, PtdIns4P 및 PtdIns(4,5)P2를 인산화 하는 포스파티딜 이노시톨 -4,5- 비스 포스페이트 3- 키나제, 촉매 서브 유닛 알파(phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; PIK3CA) 단백질을 코딩하는 유전자이다. 여기서, 상기 PIK3CA 단백질은 서열번호 10의 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the PIK3CA gene uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (phosphatidylinositol-4,5-) It is a gene encoding a bisphosphate 3-kinase, catalytic subunit alpha; PIK3CA) protein. Here, the PIK3CA protein may consist of the amino acid sequence of SEQ ID NO: 10, but is not limited thereto.
본 발명에서, 상기 PTK2 유전자는 세포 접착 및 확산과 관계되는 PTK2 단백질 티로신 키나아제 2 단백질을 코딩하는 유전자이다. 여기서, 상기 PTK2 단백질 티로신 키나아제 2 단백질은 서열번호 11의 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the PTK2 gene is a gene encoding the PTK2
본 발명에서, 상기 RB1 유전자는 세포주기 진행을 억제하는 망막 모세포종 단백질을 코딩하는 유전자이다. 여기서, 상기 망막 모세포종 단백질은 서열번호 12의 아미노산 서열로 이루어진 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the RB1 gene is a gene encoding a retinoblastoma protein that inhibits cell cycle progression. Here, the retinoblastoma protein may consist of the amino acid sequence of SEQ ID NO: 12, but is not limited thereto.
본 발명에서, 상기 "돌연변이"는 기존 유전자의 염기 순서에 영구적인 변화가 있는 것으로, 염색체 구조나 수의 변화이거나 하나 또는 몇 개의 뉴클레오티드의 변화가 있는 것이라면 제한없이 포함될 수 있다. 구체적인 예를 들면, 상기 돌연변이는 결실(deletion), 중복(duplication), 역위(inversion), 전좌(translocation), 염기 치환(base substitution), 삽입(insertion) 및 융합(fusion)에서 선택된 하나 이상일 수 있으나, 이에 제한되지는 않는다.In the present invention, the "mutation" refers to a permanent change in the nucleotide sequence of an existing gene, and may be included without limitation as long as there is a change in the chromosomal structure or number or a change in one or several nucleotides. As a specific example, the mutation may be one or more selected from deletion, duplication, inversion, translocation, base substitution, insertion, and fusion. , but not limited thereto.
본 발명에서, 상기 "결실(deletion)"은 염색체 또는 뉴클레오티드의 일부가 손실된 경우일 수 있다.In the present invention, the "deletion" may be a case in which a part of a chromosome or a nucleotide is lost.
본 발명에서 상기 "중복(duplication)"은 정상적인 염색체에 비해 염색체의 일부가 중복된 경우일 수 있다.In the present invention, the "duplication" may be a case in which a portion of a chromosome is duplicated compared to a normal chromosome.
본 발명에서 상기 "역위(inversion)"는 염색체의 일부 구간이 잘린 다음, 잘린 염색체 부위가 180도 회전하여 다시 연결되는 돌연변이일 수 있다.In the present invention, the "inversion" may be a mutation in which a portion of a chromosome is cut and then the cut chromosome is rotated 180 degrees to reconnect.
본 발명에서 상기 "전좌(translocation)"는 염색체 이상 중의 하나이며 비상동 염색체(nonhomologous chromosome) 사이에 염색체 부분끼리 서로 맞교환이 일어나서 생긴 것일 수 있다.In the present invention, the "translocation" is one of chromosomal abnormalities, and may be caused by exchange of chromosomal parts between nonhomologous chromosomes.
본 발명에서 상기 "염기 치환(base substitution)"은 DNA 분자 중에서 어느 염기가 다른 염기에 의하여 바뀌어지는 것일 수 있다.In the present invention, the "base substitution" may be one in which a base in a DNA molecule is replaced by another base.
본 발명에서 상기 "삽입(insertion)"은 한 염색체가 절단되고 그 사이에 다른 염색체 절편이 삽입되는 것일 수 있다.In the present invention, the "insertion" may mean that one chromosome is cut and another chromosome segment is inserted therebetween.
본 발명에서 상기 "융합(insertion)"은 독립적이었던 두 유전자로 형성된 하이브리드 유전자로, 전좌 또는 결실의 결과로 발생할 수 있다.In the present invention, the "fusion (insertion)" is a hybrid gene formed of two independent genes, and may occur as a result of translocation or deletion.
본 발명에서, 상기 루미널 A(luminal A) 아형은 SPOP 돌연변이 및 PRDM1 결실 중 적어도 하나를 포함하고, 바람직하게는 SPOP 돌연변이 및 PRDM1 결실을 포함하고, ETS 융합을 포함하지 않는 것일 수 있다. In the present invention, the luminal A subtype may include at least one of a SPOP mutation and a PRDM1 deletion, preferably include a SPOP mutation and a PRDM1 deletion, and not include an ETS fusion.
본 발명에서, 상기 루미널 S(luminal S) 아형은 ETS 융합 및 PTEN 결실을 포함하고, TP53 돌연변이를 포함하지 않는 것일 수 있다. In the present invention, the luminal S subtype may include an ETS fusion and a PTEN deletion, but not include a TP53 mutation.
본 발명에서, 상기 AVPC-I 아형은 TP53 돌연변이를 포함하고, PIK3CA 돌연변이를 포함하지 않는 것일 수 있고, 바람직하게는 ETS 융합, PTEN 결실 및 TP53 돌연변이를 포함하고, PIK3CA 돌연변이를 포함하지 않는 것일 수 있다. In the present invention, the AVPC-I subtype may include a TP53 mutation and not a PIK3CA mutation, and preferably include an ETS fusion, a PTEN deletion and a TP53 mutation, but not a PIK3CA mutation. .
본 발명에서, 상기 AVPC-M 아형은 PIK3CA 돌연변이를 포함하고, 바람직하게는 PIK3CA 돌연변이, ETS 융합, PTEN 결실 및 TP53 돌연변이를 포함하는 것일 수 있다. In the present invention, the AVPC-M subtype may include a PIK3CA mutation, preferably a PIK3CA mutation, an ETS fusion, a PTEN deletion, and a TP53 mutation.
본 발명에서, 상기 TP53 돌연변이는 TP53 결실인 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the TP53 mutation may be a TP53 deletion, but is not limited thereto.
본 발명에서 상기 유전자의 돌연변이 여부를 검출하거나 상기 유전자의 발현 정도를 확인하는 분석 방법으로는 역전사 중합효소반응(RT-PCR), 경쟁적 역전사 중합효소반응(Competitive RT-PCR), 실시간 역전사 중합효소반응(Real-time RT-PCR), RNase 보호 분석법(RPA; RNase protection assay), 노던 블랏팅(Northern blotting), DNA 칩 및 RNA 시퀸싱으로 이루어진 군에서 선택된 1종 이상을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, as an analysis method for detecting whether the gene is mutated or confirming the expression level of the gene, reverse transcription polymerase reaction (RT-PCR), competitive reverse transcription polymerase reaction (Competitive RT-PCR), real-time reverse transcription polymerase reaction (Real-time RT-PCR), RNase protection assay (RPA), Northern blotting (Northern blotting), may include one or more selected from the group consisting of DNA chip and RNA sequencing, but is limited thereto it's not going to be
본 발명에서, 상기 유전자의 돌연변이 여부를 검출하거나 상기 유전자의 발현 수준을 측정하는 제제는, 상기 유전자 또는 상기 유전자의 전사체에 특이적으로 결합하는 프라이머, 프로브 및 안티센스 뉴클레오티드로 이루어진 군에서 선택된 1종 이상을 포함할 수 있다.In the present invention, the agent for detecting whether the gene is mutated or measuring the expression level of the gene is one selected from the group consisting of a primer, a probe, and an antisense nucleotide that specifically binds to the gene or a transcript of the gene may include more than one.
본 발명에서 상기 "프라이머"는 표적 유전자 서열을 인지하는 단편으로서, 정방향 및 역방향의 프라이머 쌍을 포함하나, 바람직하게는, 특이성 및 민감성을 가지는 분석 결과를 제공하는 프라이머 쌍이다. 프라이머의 핵산 서열이 시료 내 존재하는 비-표적 서열과 불일치하는 서열이어서, 상보적인 프라이머 결합 부위를 함유하는 표적 유전자 서열만 증폭하고 비특이적 증폭을 유발하지 않는 프라이머일 때, 높은 특이성이 부여될 수 있다.In the present invention, the "primer" is a fragment recognizing a target gene sequence, including a pair of forward and reverse primers, but preferably a primer pair that provides analysis results having specificity and sensitivity. When the nucleic acid sequence of the primer is a sequence that is inconsistent with a non-target sequence present in the sample, and thus amplifies only the target gene sequence containing the complementary primer binding site and does not cause non-specific amplification, high specificity can be conferred. .
본 발명에서 상기 "프로브"란 시료 내의 검출하고자 하는 표적 물질과 특이적으로 결합할 수 있는 물질을 의미하며, 상기 결합을 통하여 특이적으로 시료 내의 표적 물질의 존재를 확인할 수 있는 물질을 의미한다. 프로브의 종류는 당 업계에서 통상적으로 사용되는 물질로서 제한은 없으나, 바람직하게는 PNA(peptide nucleic acid), LNA(locked nucleic acid), 펩타이드, 폴리펩타이드, 단백질, RNA 또는 DNA일 수 있으며, 가장 바람직하게는 PNA이다. 보다 구체적으로, 상기 프로브는 바이오 물질로서 생물에서 유래되거나 이와 유사한 것 또는 생체 외에서 제조된 것을 포함하는 것으로, 예를 들어, 효소, 단백질, 항체, 미생물, 동식물 세포 및 기관, 신경세포, DNA, 및 RNA일 수 있으며, DNA는 cDNA, 게놈 DNA, 올리고뉴클레오타이드를 포함하며, RNA는 게놈 RNA, mRNA, 올리고뉴클레오타이드를 포함하며, 단백질의 예로는 항체, 항원, 효소, 펩타이드 등을 포함할 수 있다.In the present invention, the term "probe" refers to a substance capable of specifically binding to a target substance to be detected in a sample, and refers to a substance capable of specifically confirming the presence of a target substance in a sample through the binding. The type of probe is not limited as a material commonly used in the art, but preferably PNA (peptide nucleic acid), LNA (locked nucleic acid), peptide, polypeptide, protein, RNA or DNA, and most preferably It is PNA. More specifically, the probe is a biomaterial derived from or similar thereto, or manufactured in vitro, for example, enzymes, proteins, antibodies, microorganisms, animal and plant cells and organs, neurons, DNA, and It may be RNA, DNA includes cDNA, genomic DNA, and oligonucleotides, RNA includes genomic RNA, mRNA, and oligonucleotides, and examples of proteins include antibodies, antigens, enzymes, peptides, and the like.
본 발명에서 상기 "LNA(Locked nucleic acids)"란, 2'-O, 4'-C 메틸렌 브릿지를 포함하는 핵산 아날로그를 의미한다 [J Weiler, J Hunziker and J Hall Gene Therapy (2006) 13, 496.502]. LNA 뉴클레오사이드는 DNA와 RNA의 일반적 핵산 염기를 포함하며, Watson-Crick 염기 쌍 규칙에 따라 염기 쌍을 형성할 수 있다. 하지만, 메틸렌 브릿지로 인한 분자의 'locking'으로 인해, LNA는 Watson-Crick 결합에서 이상적 형상을 형성하지 못하게 된다. LNA가 DNA 또는 RNA 올리고뉴클레오티드에 포함되면, LNA는 보다 빠르게 상보적 뉴클레오티드 사슬과 쌍을 이루어 이중 나선의 안정성을 높일 수 있다. 본 발명에서 상기 "안티센스"는 안티센스 올리고머가 왓슨-크릭 염기쌍 형성에 의해 RNA 내의 표적 서열과 혼성화되어, 표적서열 내에서 전형적으로 mRNA와 RNA: 올리고머 헤테로이중체의 형성을 허용하는, 뉴클레오티드 염기의 서열 및 서브유닛간 백본을 갖는 올리고머를 의미한다. 올리고머는 표적 서열에 대한 정확한 서열 상보성 또는 근사 상보성을 가질 수 있다.In the present invention, the "LNA (Locked nucleic acids)" means a nucleic acid analog including a 2'-O, 4'-C methylene bridge [J Weiler, J Hunziker and J Hall Gene Therapy (2006) 13, 496.502) ]. LNA nucleosides include common nucleic acid bases in DNA and RNA, and can form base pairs according to Watson-Crick base pairing rules. However, due to the 'locking' of the molecule due to the methylene bridge, the LNA does not form the ideal shape in the Watson-Crick bond. When LNAs are incorporated into DNA or RNA oligonucleotides, LNAs can pair with complementary nucleotide chains more rapidly, increasing the stability of the double helix. In the present invention, the "antisense" means that the antisense oligomer is hybridized with a target sequence in RNA by Watson-Crick base pairing, and typically mRNA and RNA in the target sequence: A sequence of nucleotide bases allowing the formation of an oligomeric heteroduplex. and oligomers having an inter-subunit backbone. An oligomer may have exact sequence complementarity or approximate complementarity to a target sequence.
본 발명에 따른 상기 유전자에 해당하는 유전자의 서열 정보는 알려져 있으므로, 당업자라면 이를 바탕으로 상기 유전자에 특이적으로 결합하는 프라이머, 프로브 또는 안티센스 뉴클레오티드를 용이하게 디자인할 수 있을 것이다.Since sequence information of the gene corresponding to the gene according to the present invention is known, those skilled in the art will be able to easily design a primer, probe or antisense nucleotide that specifically binds to the gene based on this.
본 발명에서, 상기 유전자의 돌연변이 여부나 상기 유전자의 발현 수준은 상기 유전자에 의해 코딩되는 단백질의 발현 수준으로 검출되거나 측정될 수 있다. In the present invention, whether the gene is mutated or the expression level of the gene may be detected or measured as the expression level of a protein encoded by the gene.
본 발명에서, 상기 유전자의 돌연변이 또는 상기 유전자의 발현에 의한 단백질의 발현 수준을 검출, 측정 또는 비교 분석하는 방법으로는 단백질 칩 분석, 면역측정법, 리간드 바인딩 어세이, MALDI-TOF(Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry) 분석, SELDI-TOF(Sulface Enhanced Laser Desorption/Ionization Time of Flight Mass Spectrometry) 분석, 방사선 면역분석, 방사 면역 확산법, 오우크테로니 면역 확산법, 로케트 면역전기영동, 조직면역 염색, 보체 고정 분석법, 2차원 전기영동 분석, 액상 크로마토그래피-질량분석(liquid chromatography-Mass Spectrometry, LC-MS), LC-MS/MS(liquid chromatography-Mass Spectrometry/Mass Spectrometry), 웨스턴 블랏팅 및 ELISA(enzyme linked immunosorbentassay)로 이루어진 군에서 선택된 1종 이상을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, as a method for detecting, measuring, or comparing the expression level of a protein by mutation of the gene or expression of the gene, protein chip analysis, immunoassay, ligand binding assay, MALDI-TOF (Matrix Assisted Laser Desorption) /Ionization Time of Flight Mass Spectrometry) analysis, SELDI-TOF (Sulface Enhanced Laser Desorption/Ionization Time of Flight Mass Spectrometry) analysis, radioimmunoassay, radioimmunodiffusion method, Oukteroni immunodiffusion method, rocket immunoelectrophoresis, tissue immunity Staining, complement fixation assay, two-dimensional electrophoresis analysis, liquid chromatography-Mass Spectrometry (LC-MS), liquid chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS), Western blotting and It may include one or more selected from the group consisting of ELISA (enzyme linked immunosorbent assay), but is not limited thereto.
본 발명에서 상기 유전자의 돌연변이 또는 상기 유전자의 발현에 의한 단백질의 발현 수준을 측정하는 제제는 상기 단백질에 특이적으로 결합하는 항체, 올리고펩타이드, 리간드, PNA(peptide nucleic acid) 및 앱타머(aptamer)로 이루어진 군에서 선택된 1종 이상을 포함할 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the agent for measuring the expression level of a protein by mutation of the gene or expression of the gene is an antibody, oligopeptide, ligand, PNA (peptide nucleic acid) and aptamer that specifically binds to the protein. It may include one or more selected from the group consisting of, but is not limited thereto.
본 발명에서 상기 "항체"는 항원과 특이적으로 결합하여 항원-항체 반응을 일으키는 물질을 가리킨다. 본 발명의 목적상, 항체는 상기 단백질들 각각에 대해 특이적으로 결합하는 항체를 의미한다. 본 발명의 항체는 다클론 항체, 단클론 항체 및 재조합 항체를 모두 포함한다. 상기 항체는 당업계에 널리 공지된 기술을 이용하여 용이하게 제조될 수 있다. 예를 들어, 다클론 항체는 상기 단백질의 항원을 동물에 주사하고 동물로부터 채혈하여 항체를 포함하는 혈청을 수득하는 과정을 포함하는 당 업계에 널리 공지된 방법에 의해 생산될 수 있다. 이러한 다클론 항체는 염소, 토끼, 양, 원숭이, 말, 돼지, 소, 개 등의 임의의 동물로부터 제조될 수 있다. 또한, 단클론 항체는 당 업계에 널리 공지된 하이브리도마 방법(hybridoma method; Kohler 및 Milstein (1976) European Journal of Immunology 6:511-519 참조), 또는 파지 항체 라이브러리 기술(Clackson et al, Nature, 352:624-628, 1991; Marks et al, J. Mol. Biol., 222:58, 1-597, 1991 참조)을 이용하여 제조될 수 있다. 상기 방법으로 제조된 항체는 겔 전기영동, 투석, 염 침전, 이온교환 크로마토그래피, 친화성 크로마토그래피 등의 방법을 이용하여 분리, 정제될 수 있다. 또한, 본 발명의 항체는 2개의 전장의 경쇄 및 2개의 전장의 중쇄를 갖는 완전한 형태뿐만 아니라, 항체 분자의 기능적인 단편을 포함한다. 항체 분자의 기능적인 단편이란, 적어도 항원 결합 기능을 보유하고 있는 단편을 의미하며, Fab, F(ab'), F(ab')2 및 Fv 등이 있다.In the present invention, the "antibody" refers to a substance that specifically binds to an antigen and causes an antigen-antibody reaction. For the purposes of the present invention, an antibody refers to an antibody that specifically binds to each of the above proteins. Antibodies of the present invention include polyclonal antibodies, monoclonal antibodies and recombinant antibodies. The antibody can be readily prepared using techniques well known in the art. For example, the polyclonal antibody can be produced by a method well known in the art, including the process of injecting an antigen of the protein into an animal and collecting blood from the animal to obtain a serum containing the antibody. Such polyclonal antibodies can be prepared from any animal such as goat, rabbit, sheep, monkey, horse, pig, cow, dog, and the like. In addition, monoclonal antibodies can be prepared using the hybridoma method well known in the art (see Kohler and Milstein (1976) European Journal of Immunology 6:511-519), or the phage antibody library technology (Clackson et al, Nature, 352). :624-628, 1991; Marks et al, J. Mol. Biol., 222:58, 1-597, 1991). The antibody prepared by the above method may be separated and purified using methods such as gel electrophoresis, dialysis, salt precipitation, ion exchange chromatography, and affinity chromatography. In addition, the antibodies of the present invention include functional fragments of antibody molecules as well as complete forms having two full-length light chains and two full-length heavy chains. A functional fragment of an antibody molecule means a fragment having at least an antigen-binding function, and includes Fab, F(ab'), F(ab')2 and Fv.
본 발명에서 상기 "올리고펩타이드"는 펩타이드로 2 내지 20 개의 아미노산으로 구성되며 디 펩타이드, 트리 펩타이드, 테트라 펩타이드 및 펜타 펩타이드를 포함할 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the "oligopeptide" is a peptide consisting of 2 to 20 amino acids and may include a dipeptide, a tripeptide, a tetrapeptide, and a pentapeptide, but is not limited thereto.
본 발명에 상기 "PNA(Peptide Nucleic Acid)"는 인공적으로 합성된, DNA 또는 RNA와 비슷한 중합체를 가리키며, 1991년 덴마크 코펜하겐 대학교의 Nielsen, Egholm, Berg와 Buchardt 교수에 의해 처음으로 소개되었다. DNA는 인산-리보스당 골격을 갖는데 반해, PNA는 펩타이드 결합에 의해 연결된 반복된 N-(2-아미노에틸)-글리신 골격을 가지며, 이로 인해 DNA 또는 RNA에 대한 결합력과 안정성이 크게 증가되어 분자 생물학, 진단 분석 및 안티센스 치료법에 사용되고 있다. PNA는 문헌[Nielsen PE, Egholm M, Berg RH, Buchardt O (December 1991). "Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide". Science 254 (5037): 1497-1500]에 상세하게 개시되어 있다.In the present invention, "PNA (Peptide Nucleic Acid)" refers to an artificially synthesized, DNA or RNA-like polymer, and was first introduced by Professors Nielsen, Egholm, Berg and Buchardt of the University of Copenhagen, Denmark in 1991. Whereas DNA has a phosphate-ribose sugar backbone, PNA has a repeated N-(2-aminoethyl)-glycine backbone linked by peptide bonds, which greatly increases binding strength and stability to DNA or RNA, resulting in molecular biology , diagnostic assays and antisense therapy. PNA is described in Nielsen PE, Egholm M, Berg RH, Buchardt O (December 1991). "Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide". Science 254 (5037): 1497-1500.
본 발명에서 상기 "앱타머"는 올리고핵산 또는 펩타이드 분자이며, 앱타머의 일반적인 내용은 문헌[Bock LC et al., Nature 355(6360):5646(1992); Hoppe-Seyler F, Butz K "Peptide aptamers: powerful new tools for molecular medicine". J Mol Med. 78(8):42630(2000); Cohen BA, Colas P, Brent R. "An artificial cell-cycle inhibitor isolated from a combinatorial library". Proc Natl Acad Sci USA. 95(24): 142727(1998)]에 상세하게 개시되어 있다.In the present invention, the "aptamer" is an oligonucleic acid or peptide molecule, and the general description of the aptamer is described in Bock LC et al., Nature 355(6360):5646(1992); Hoppe-Seyler F, Butz K "Peptide aptamers: powerful new tools for molecular medicine". J Mol Med. 78(8):42630(2000); Cohen BA, Colas P, Brent R. "An artificial cell-cycle inhibitor isolated from a combinatorial library". Proc Natl Acad Sci USA. 95(24): 142727 (1998).
본 발명에서, 상기 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형에서, 각 아형 별 상이한 유전자 발현 패턴을 보일 수 있다. In the present invention, in the luminal A subtype, luminal S subtype, AVPC-I subtype, and AVPC-M subtype, different gene expression patterns for each subtype may be exhibited.
본 발명에서 각 아형 별 상이한 발현 패턴을 보이는 유전자로는 KLK3, ACP3, ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B, PCA3, CDC20, MYBL2, COL10A1, ALOX15, ANKRD34B, KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B, TRPM8, HDAC9, ETV1, BEX1, ATP1A1, ERG, APOD, TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1, ALOX15B, ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B, COL2A1, NIPAL3, TSPAN19, RFPL1S, CPM, NEFH, CEACAM5, YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 및 CHGA로 이루어진 군에서 선택된 1종 이상일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, genes showing different expression patterns for each subtype include KLK3, ACP3, ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B, PCA3, CDC20, MYBL2, COL10A1, ALOX15, ANKRD34B, KLK2, MESP1, KLK4, SLC45A3, ABCC4,A3, FAM3B, TRPM8, HDAC9, ETV1, BEX1, ATP1A1, ERG, APOD, TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1, ALOX15B, ANKRD6, PDE8B, ERG, LINC024PAN18, ALOX15, ANKRD34B, NOLTS It may be one or more selected from the group consisting of RFPL1S, CPM, NEFH, CEACAM5, YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 and CHGA, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 KLK3 및 ACP3을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include KLK3 and ACP3, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B 및 PCA3 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B and PCA3 genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 CDC20, MYBL2, COL10A1, ALOX15 및 ANKRD34B 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from CDC20, MYBL2, COL10A1, ALOX15 and ANKRD34B genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B 및 TRPM8 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B and TRPM8 genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 HDAC9, ETV1, BEX1, ATP1A1, ERG 및 APOD 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from HDAC9, ETV1, BEX1, ATP1A1, ERG and APOD genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1 및 ALOX15B 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1 and ALOX15B genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B 및 COL2A1 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B and COL2A1 genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 NIPAL3, TSPAN19, RFPL1S, CPM, NEFH 및 CEACAM5 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from NIPAL3, TSPAN19, RFPL1S, CPM, NEFH and CEACAM5 genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 및 CHGA 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 and CHGA genes, but is not limited thereto.
본 발명의 일 예시에서, 상기 루미널 A(luminal A) 및 상기 루미널 S(luminal S) 아형 중 적어도 하나는 상기 AVPC-I 아형 및 상기 AVPC-M 아형 중 적어도 하나에 비하여 ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B 및 PCA3로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In an example of the present invention, at least one of the luminal A and the luminal S subtype is ANPEP, RLN1, PCAT4 compared to at least one of the AVPC-I subtype and the AVPC-M subtype , PCGEM1, ALOX15B, and one or more genes selected from the group consisting of PCA3 may be expressed at a higher level.
본 발명의 다른 예시에서, 상기 AVPC-I 아형 및 상기 AVPC-M 아형 중 적어도 하나는 상기 루미널 A(luminal A) 및 상기 루미널 S(luminal S) 아형 중 적어도 하나에 비하여 CDC20, MYBL2, COL10A1, ALOX15 및 ANKRD34B로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다. In another example of the present invention, at least one of the AVPC-I subtype and the AVPC-M subtype is CDC20, MYBL2, COL10A1 compared to at least one of the luminal A and luminal S subtypes , one or more genes selected from the group consisting of ALOX15 and ANKRD34B may be expressed at a higher level.
본 발명의 또 다른 예시에서, 상기 루미널 A(luminal A) 아형은 상기 AVPC-I 아형에 비하여 KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B 및 TRPM8로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In another example of the present invention, the luminal A subtype has a higher level of one or more genes selected from the group consisting of KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B and TRPM8 compared to the AVPC-I subtype. level can be expressed.
본 발명의 또 다른 예시에서, 상기 AVPC-I 아형은 상기 루미널 A(luminal A) 아형에 비하여 HDAC9, ETV1, BEX1, ATP1A1, ERG 및 APOD로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In another example of the present invention, the AVPC-I subtype has a higher level of one or more genes selected from the group consisting of HDAC9, ETV1, BEX1, ATP1A1, ERG and APOD compared to the luminal A subtype. can be expressed.
본 발명의 또 다른 예시에서, 상기 루미널 A(luminal A) 아형은 상기 루미널 S(luminal S) 아형에 비하여 TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1 및 ALOX15B로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In another example of the present invention, the luminal A subtype is one selected from the group consisting of TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1 and ALOX15B compared to the luminal S subtype. More than one species of genes may be expressed at higher levels.
본 발명의 또 다른 예시에서, 상기 루미널 S(luminal S) 아형은 상기 루미널 A(luminal A) 아형에 비하여 ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B 및 COL2A1로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In another example of the present invention, the luminal S subtype is at least one selected from the group consisting of ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B and COL2A1 compared to the luminal A subtype. Genes can be expressed at higher levels.
본 발명의 또 다른 예시에서, 상기 AVPC-I 아형은 상기 AVPC-M 아형에 비하여 NIPAL3, TSPAN19, RFPL1S, CPM, NEFH 및 CEACAM5로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In another example of the present invention, in the AVPC-I subtype, one or more genes selected from the group consisting of NIPAL3, TSPAN19, RFPL1S, CPM, NEFH and CEACAM5 may be expressed at a higher level than the AVPC-M subtype. .
본 발명의 또 다른 예시에서, 상기 AVPC-M 아형은 상기 AVPC-I 아형에 비하여 YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 및 CHGA로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In another example of the present invention, the AVPC-M subtype has a higher level of one or more genes selected from the group consisting of YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 and CHGA compared to the AVPC-I subtype. can be expressed.
본 발명에서 상기 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형 각각은 상기 아형을 가진 목적하는 개체로부터 분리된 생물학적 시료, 바람직하게는 혈청 내 PAP 단백질의 발현 수준에 대한 PSA 단백질의 발현 수준의 비율(PSA/PAP)이 서로 동일하거나 상이할 수 있다.In the present invention, each of the luminal A subtype, the luminal S subtype, the AVPC-I subtype and the AVPC-M subtype relates to the expression level of PAP protein in a biological sample, preferably serum, isolated from a subject having the subtype. The ratio of the expression level of the PSA protein (PSA/PAP) may be the same or different from each other.
본 발명의 일 예시에서, 루미널 A 아형은 상기 루미널 A 아형을 가진 목적하는 개체로부터 분리된 생물학적 시료, 바람직하게는 혈청 내 PAP 단백질의 발현 수준에 대한 PSA 단백질의 발현 수준의 비율(PSA/PAP)이 20 초과의 값일 수 있으나, 이에 제한되는 것은 아니다.In one example of the present invention, the luminal A subtype is the ratio of the expression level of PSA protein to the expression level of PAP protein in a biological sample, preferably serum, isolated from a subject having the luminal A subtype (PSA/ PAP) may be a value greater than 20, but is not limited thereto.
본 발명의 다른 예시에서, 루미널 S 아형은 상기 루미널 S 아형을 가진 목적하는 개체로부터 분리된 생물학적 시료, 바람직하게는 혈청 내 PAP 단백질의 발현 수준에 대한 PSA 단백질의 발현 수준의 비율(PSA/PAP)이 20 이하의 값일 수 있으나, 이에 제한되는 것은 아니다.In another example of the present invention, the luminal S subtype is the ratio of the expression level of PSA protein to the expression level of PAP protein in a biological sample, preferably serum, isolated from a subject having the luminal S subtype (PSA/ PAP) may be a value of 20 or less, but is not limited thereto.
본 발명의 또 다른 예시에서, AVPC-I 아형은 상기 AVPC-I 아형을 가진 목적하는 개체로부터 분리된 생물학적 시료, 바람직하게는 혈청 내 PAP 단백질의 발현 수준에 대한 PSA 단백질의 발현 수준의 비율(PSA/PAP)이 20 이하의 값일 수 있으나, 이에 제한되는 것은 아니다.In another example of the present invention, the AVPC-I subtype is the ratio of the expression level of PSA protein to the expression level of PAP protein in a biological sample, preferably serum, isolated from a target subject having the AVPC-I subtype (PSA). /PAP) may be a value of 20 or less, but is not limited thereto.
본 발명의 또 다른 예시에서, AVPC-M 아형은 상기 AVPC-M 아형을 가진 목적하는 개체로부터 분리된 생물학적 시료, 바람직하게는 혈청 내 PAP 단백질의 발현 수준에 대한 PSA 단백질의 발현 수준의 비율(PSA/PAP)이 20 초과의 값일 수 있으나, 이에 제한되는 것은 아니다.In another example of the present invention, the AVPC-M subtype is the ratio of the expression level of PSA protein to the expression level of PAP protein in a biological sample, preferably serum, isolated from a subject having said AVPC-M subtype (PSA). /PAP) may be a value greater than 20, but is not limited thereto.
본 발명에서 상기 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형은 각각 항암제에 대하여 상이한 감수성을 보일 수 있다. In the present invention, the luminal subtype A, luminal S subtype, AVPC-I subtype, and AVPC-M subtype may show different sensitivities to anticancer agents, respectively.
본 발명에서 각 아형 별 상이한 감수성을 보이는 항암제로는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 소라페닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 데시타빈, 카페시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 아나스트로졸, 레트로졸, 보로졸, 로무스틴, 보리노스텟, 엔티노스텟, 카르무스틴, 안드로겐 억제제 및 도세탁셀에서 선택된 어느 하나 이상인 것일 수 있고, 바람직하게는 도세탁셀(docetaxel) 또는 안드로겐 억제제(androgen inhibitor)일 수 있으나, 이에 제한되는 것은 아니다. 여기서, 상기 안드로겐 억제제는 비칼루타미드, 플루타미드, 칼루스테론, 드로모스타놀론,프로피오네이트, 에피티오스타놀, 고세렐린, 류프롤리드, 메피티오스탄, 닐루타미드, 테스토락톤 및 트리로스탄으로 이루어진 군으로부터 선택되는 적어도 하나인 것일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, anticancer agents showing different sensitivities for each subtype include nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosu Tinib, axitinib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, viscumalbum, aspart Laginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tusetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine , alprostadil, holmium nitrate chitosan, gemcitabine, doxyfluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, fluoro Uracil, fludagabine, enocitabine, decitabine, capecitabine, mercaptopurine, thioguanine, cladribine, carmofer, raltitrexed, irinotecan, belotecan, topotecan, vinorelbine, etoposide, Vincristine, Vinblastine, Teniposide, Doxorubicin, Idarubicin, Epirubicin, Mitoxantrone, Mitomycin, Bleromycin, Daunorubicin, Dactinomycin, Pyrarubicin, Aclarubicin, Pep Romaycin, temsirolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melparan, altretmine, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, Tretonin, exemestane, aminoglutethimide, anagrelide, nabelbine, fadrazole, tamoxifen, toremifene, anastrozole, letrozole, vorozole, lomustine, vorinostat, entinostat , may be any one or more selected from carmustine, androgen inhibitors and docetaxel, preferably docetaxel (docetaxel) or androgen inhibitors (androgen inhibitor), but is not limited thereto. Here, the androgen inhibitor is bicalutamide, flutamide, calusterone, dromostanolone, propionate, epithiostanol, goserelin, leuprolide, mepitiostan, nilutamide, testolactone and tri It may be at least one selected from the group consisting of rostan, but is not limited thereto.
본 발명의 일 예시에서 상기 루미널 A 아형은 도세탁셀(docetaxel)에 내성을 가지며, 안드로겐 억제제(androgen inhibitor)에 감수성을 가지는 것일 수 있다.In an example of the present invention, the luminal A subtype may have resistance to docetaxel and sensitivity to androgen inhibitors.
본 발명의 다른 예시에서 상기 루미널 S 아형은 도세탁셀에 감수성을 가지며, 안드로겐 억제제에 감수성을 가지는 것일 수 있다.In another example of the present invention, the luminal S subtype may be sensitive to docetaxel and sensitive to androgen inhibitors.
본 발명의 또 다른 예시에서 상기 AVPC-I 아형은 도세탁셀에 감수성을 가지며, 안드로겐 억제제에 내성을 가지는 것일 수 있다.In another example of the present invention, the AVPC-I subtype may be sensitive to docetaxel and resistant to androgen inhibitors.
본 발명의 또 다른 예시에서 AVPC-M 아형은 도세탁셀에 내성을 가지며, 안드로겐 억제제에 내성을 가지는 것일 수 있다.In another example of the present invention, the AVPC-M subtype may be resistant to docetaxel and resistant to androgen inhibitors.
본 발명의 다른 구현 예에 따르면, 목적하는 개체의 전립선암을 루미널 A(luminal A) 아형, 루미널 S(luminal S) 아형, 면역 침윤성/혈관형성을 띄는 공격적인 변이형 전립선암(aggressive variant PCs immune-infiltrative/angiogenic; AVPC-I) 아형 및 MYC 활성을 띄는 공격적인 변이형 전립선암(aggressive variant PCs Myc active; AVPC-M) 아형으로 분류하는 연산부를 포함하는, 전립선암의 아형 분류 장치에 관한 것이다. According to another embodiment of the present invention, the prostate cancer of a subject is luminal A (luminal A) subtype, luminal S (luminal S) subtype, and aggressive variant PCs exhibiting immune invasiveness/angiogenesis. It relates to a subtype classification device for prostate cancer, comprising an immune-infiltrative/angiogenic; AVPC-I) subtype and an operating unit for classifying it into an aggressive variant PCs Myc active (AVPC-M) subtype with MYC activity. .
본 발명의 아형 분류 장치는, 상기 목적하는 개체의 생물학적 시료에서 SPOP, PRDM1, ETS, PTEN, TP53, PIK3CA, PTK2 및 RB1 유전자에서 선택된 적어도 하나의 돌연변이 여부를 검출하는 검출부를 더 포함할 수 있다. The subtype classification apparatus of the present invention may further include a detection unit for detecting whether at least one mutation selected from SPOP, PRDM1, ETS, PTEN, TP53, PIK3CA, PTK2 and RB1 genes in the biological sample of the target individual.
본 발명에서 상기 돌연변이는 결실(deletion), 중복(duplication), 역위(inversion), 전좌(translocation), 염기 치환(base substitution), 삽입(insertion) 및 융합(fusion)에서 선택된 하나 이상일 수 있으나, 이에 제한되지는 않는다.In the present invention, the mutation may be one or more selected from deletion, duplication, inversion, translocation, base substitution, insertion and fusion, but Not limited.
본 발명의 상기 검출부에서 상기 유전자의 돌연변이 여부 또는 상기 유전자의 발현 정도를 측정하는 방법으로는 역전사 중합효소반응(RT-PCR), 경쟁적 역전사 중합효소반응(Competitive RT-PCR), 실시간 역전사 중합효소반응(Real-time RT-PCR), RNase 보호 분석법(RPA; RNase protection assay), 노던 블랏팅(Northern blotting), DNA 칩 및 RNA 시퀸싱으로 이루어진 군에서 선택된 1종 이상의 방법에 의해 수행될 수 있으나, 이에 제한되는 것은 아니다.Methods for measuring whether the gene is mutated or the expression level of the gene in the detection unit of the present invention include reverse transcription polymerase reaction (RT-PCR), competitive reverse transcription polymerase reaction (Competitive RT-PCR), real-time reverse transcription polymerase reaction (Real-time RT-PCR), RNase protection assay (RPA; RNase protection assay), Northern blotting, DNA chip and RNA sequencing may be performed by one or more methods selected from the group consisting of, However, the present invention is not limited thereto.
본 발명의 상기 검출부에서 상기 유전자의 돌연변이 여부를 검출하거나 상기 유전자의 발현 수준을 측정하기 위한 제제로는, 상기 유전자 또는 상기 유전자의 전사체에 특이적으로 결합하는 프라이머, 프로브 및 안티센스 뉴클레오티드로 이루어진 군에서 선택된 1종 이상을 이용할 수 있으나, 이에 제한되는 것은 아니다.As an agent for detecting whether the gene is mutated or measuring the expression level of the gene in the detection unit of the present invention, a primer, a probe, and an antisense nucleotide that specifically bind to the gene or a transcript of the gene At least one selected from may be used, but is not limited thereto.
본 발명의 검출부에서는 상기 유전자의 돌연변이 여부 또는 상기 유전자의 발현 수준을 상기 유전자에 의해 코딩되는 단백질의 발현 수준으로 검출 또는 측정할 수 있다. In the detection unit of the present invention, whether the gene is mutated or the expression level of the gene may be detected or measured as the expression level of a protein encoded by the gene.
본 발명의 검출부에서 상기 단백질의 발현 수준을 검출, 측정 또는 비교 분석하는 방법으로는 단백질 칩 분석, 면역측정법, 리간드 바인딩 어세이, MALDI-TOF(Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry) 분석, SELDI-TOF(Sulface Enhanced Laser Desorption/Ionization Time of Flight Mass Spectrometry) 분석, 방사선 면역분석, 방사 면역 확산법, 오우크테로니 면역 확산법, 로케트 면역전기영동, 조직면역 염색, 보체 고정 분석법, 2차원 전기영동 분석, 액상 크로마토그래피-질량분석(liquid chromatography-Mass Spectrometry, LC-MS), LC-MS/MS(liquid chromatography-Mass Spectrometry/ Mass Spectrometry), 웨스턴 블랏팅 및 ELISA(enzyme linked immunosorbentassay)로 이루어진 군에서 선택된 1종 이상의 방법에 의해 수행될 수 있으나, 이에 제한되는 것은 아니다.Methods for detecting, measuring, or comparatively analyzing the expression level of the protein in the detection unit of the present invention include protein chip analysis, immunoassay, ligand binding assay, and Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF) analysis. , SELDI-TOF (Sulface Enhanced Laser Desorption/Ionization Time of Flight Mass Spectrometry) analysis, radioimmunoassay, radioimmunodiffusion method, octeroni immunodiffusion method, rocket immunoelectrophoresis, tissue immunostaining, complement fixation assay, 2D electrophoresis Group consisting of electrophoretic analysis, liquid chromatography-Mass Spectrometry (LC-MS), LC-MS/MS (liquid chromatography-Mass Spectrometry/Mass Spectrometry), Western blotting and ELISA (enzyme linked immunosorbent assay) It may be performed by one or more methods selected from, but is not limited thereto.
본 발명의 검출부에서 상기 단백질의 발현 수준을 측정하는 제제로는 상기 단백질에 특이적으로 결합하는 항체, 올리고펩타이드, 리간드, PNA(peptide nucleic acid) 및 앱타머(aptamer)로 이루어진 군에서 선택된 1종 이상을 이용할 수 있으나, 이에 제한되는 것은 아니다. The agent for measuring the expression level of the protein in the detection unit of the present invention is one selected from the group consisting of an antibody, oligopeptide, ligand, PNA (peptide nucleic acid) and aptamer that specifically binds to the protein. The above may be used, but is not limited thereto.
본 발명에서, 상기 검출부에서 상기 생물학적 시료가 SPOP 돌연변이 및 PRDM1 결실 돌연변이 중 적어도 하나를 포함하고, 바람직하게는 SPOP 돌연변이 및 PRDM1 결실 돌연변이를 포함하고, ETS 융합 돌연변이를 포함하지 않는 것으로 검출되는 경우, 상기 연산부에서는 상기 목적하는 개체에서 발병한 전립선암을 루미널 A(luminal A) 아형으로 분류할 수 있다.In the present invention, when the detection unit detects that the biological sample contains at least one of a SPOP mutation and a PRDM1 deletion mutation, preferably contains a SPOP mutation and a PRDM1 deletion mutation, and does not include an ETS fusion mutation, the The calculation unit may classify the prostate cancer occurring in the target individual into a luminal A subtype.
본 발명에서, 상기 검출부에서 상기 생물학적 시료가 ETS 융합 및 PTEN 결실을 포함하고, TP53 돌연변이를 포함하지 않는 것으로 검출되는 경우, 상기 연산부에서는 상기 목적하는 개체에서 발병한 전립선암을 루미널 S(luminal S) 아형으로 분류할 수 있다.In the present invention, when the detection unit detects that the biological sample contains the ETS fusion and the PTEN deletion and does not contain the TP53 mutation, the operation unit detects prostate cancer that has occurred in the subject of interest (luminal S). ) can be classified into subtypes.
본 발명에서, 상기 검출부에서 상기 생물학적 시료가 TP53 돌연변이를 포함하고, PIK3CA 돌연변이를 포함하지 않는 것으로 검출되는 경우로, 바람직하게는 ETS 융합, PTEN 결실 및 TP53 돌연변이를 포함하고, PIK3CA 돌연변이를 포함하지 않는 것으로 검출되는 경우, 상기 연산부에서는 상기 목적하는 개체에서 발병한 전립선암을 AVPC-I 아형으로 분류할 수 있다.In the present invention, when the detection unit detects that the biological sample contains a TP53 mutation and does not contain a PIK3CA mutation, preferably includes an ETS fusion, a PTEN deletion and a TP53 mutation, but does not include a PIK3CA mutation is detected, the operation unit may classify the prostate cancer that has occurred in the target individual as an AVPC-I subtype.
본 발명에서, 상기 검출부에서 상기 생물학적 시료가 PIK3CA 돌연변이를 포함하고, 바람직하게는 PIK3CA 돌연변이, ETS 융합, PTEN 결실 및 TP53 돌연변이를 포함하는 것으로 검출되는 경우, 상기 연산부에서는 상기 목적하는 개체에서 발병한 전립선암을 AVPC-M 아형으로 분류할 수 있다.In the present invention, when the detection unit detects that the biological sample contains a PIK3CA mutation, and preferably contains a PIK3CA mutation, an ETS fusion, a PTEN deletion, and a TP53 mutation, the operation unit includes a prostate developed in the subject. Cancer can be classified as AVPC-M subtype.
본 발명에서, 상기 TP53 돌연변이는 TP53 결실인 것일 수 있으나, 이에 제한되지는 않는다.In the present invention, the TP53 mutation may be a TP53 deletion, but is not limited thereto.
본 발명에서 상기 연산부에서 분류된 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형은 각각 항암제에 대하여 상이한 감수성을 보일 수 있다. In the present invention, the luminal A subtype, the luminal S subtype, the AVPC-I subtype, and the AVPC-M subtype classified by the calculation unit may show different sensitivities to anticancer drugs, respectively.
본 발명에서 각 아형 별 상이한 감수성을 보이는 항암제로는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 소라페닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실(5FU), 플루다가빈, 에노시타빈, 데시타빈, 카페시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 아나스트로졸, 레트로졸, 보로졸, 로무스틴, 보리노스텟, 엔티노스텟, 카르무스틴, 안드로겐 억제제 및 도세탁셀에서 선택된 어느 하나 이상인 것일 수 있고, 바람직하게는 도세탁셀(docetaxel) 또는 안드로겐 억제제(androgen inhibitor)일 수 있으나, 이에 제한되는 것은 아니다. 여기서, 상기 안드로겐 억제제는 비칼루타미드, 플루타미드, 칼루스테론, 드로모스타놀론,프로피오네이트, 에피티오스타놀, 고세렐린, 류프롤리드, 메피티오스탄, 닐루타미드, 테스토락톤 및 트리로스탄으로 이루어진 군으로부터 선택되는 적어도 하나인 것일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, anticancer agents showing different sensitivities for each subtype include nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosu Tinib, axitinib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, viscumalbum, aspart Laginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tusetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine , alprostadil, holmium nitrate chitosan, gemcitabine, doxyfluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, fluoro Uracil (5FU), fludagabine, enocitabine, decitabine, capecitabine, mercaptopurine, thioguanine, cladribine, carmofer, raltitrexed, irinotecan, velotecan, topotecan, vinorelbine, etho Forsyd, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin cin, pepromycin, temsirolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melparan, altretmine, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, re Ucovorin, tretonin, exemestane, aminoglutethimide, anagrelide, nabelbine, fadrazole, tamoxifen, toremifene, anastrozole, letrozole, vorozole, lomustine, vorinostat, It may be any one or more selected from entinostat, carmustine, androgen inhibitors and docetaxel, preferably docetaxel (docetaxel) or androgen inhibitors (androgen inhibitor), but is not limited thereto. Here, the androgen inhibitor is bicalutamide, flutamide, calusterone, dromostanolone, propionate, epithiostanol, goserelin, leuprolide, mepitiostan, nilutamide, testolactone and tri It may be at least one selected from the group consisting of rostan, but is not limited thereto.
본 발명에서 상기 루미널 A 아형은 도세탁셀(docetaxel)에 내성을 가지며 안드로겐 억제제(androgen inhibitor)에 감수성을 가지는 것일 수 있다.In the present invention, the luminal A subtype may have resistance to docetaxel and sensitivity to androgen inhibitors.
본 발명에서 상기 루미널 S 아형은 도세탁셀에 감수성을 가지며 안드로겐 억제제에 감수성을 가지는 것일 수 있다.In the present invention, the luminal S subtype may be sensitive to docetaxel and sensitive to androgen inhibitors.
본 발명에서 상기 AVPC-I 아형은 도세탁셀에 감수성을 가지며, 안드로겐 억제제에 내성을 가지는 것일 수 있다.In the present invention, the AVPC-I subtype may be sensitive to docetaxel and resistant to androgen inhibitors.
본 발명에서 AVPC-M 아형은 도세탁셀에 내성을 가지며, 안드로겐 억제제에 내성을 가지는 것일 수 있다.In the present invention, the AVPC-M subtype may be resistant to docetaxel and resistant to androgen inhibitors.
또한, 본 발명에서 상기 연산부에서 분류된 상기 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형은 각각 특정 유전자에 대하여 상이한 발현 패턴을 보일 수 있다. In addition, in the present invention, the luminal A subtype, the luminal S subtype, the AVPC-I subtype, and the AVPC-M subtype classified by the operation unit may show different expression patterns for specific genes, respectively.
본 발명에서 각 아형 별 상이한 발현 패턴을 보이는 유전자로는 KLK3, ACP3, ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B, PCA3, CDC20, MYBL2, COL10A1, ALOX15, ANKRD34B, KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B, TRPM8, HDAC9, ETV1, BEX1, ATP1A1, ERG, APOD, TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1, ALOX15B, ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B, COL2A1, NIPAL3, TSPAN19, RFPL1S, CPM, NEFH, CEACAM5, YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 및 CHGA로 이루어진 군에서 선택된 1종 이상일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, genes showing different expression patterns for each subtype include KLK3, ACP3, ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B, PCA3, CDC20, MYBL2, COL10A1, ALOX15, ANKRD34B, KLK2, MESP1, KLK4, SLC45A3, ABCC4,A3, FAM3B, TRPM8, HDAC9, ETV1, BEX1, ATP1A1, ERG, APOD, TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1, ALOX15B, ANKRD6, PDE8B, ERG, LINC024PAN18, ALOX15, ANKRD34B, NOLTS It may be one or more selected from the group consisting of RFPL1S, CPM, NEFH, CEACAM5, YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 and CHGA, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 KLK3 및 ACP3을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include KLK3 and ACP3, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B 및 PCA3 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B and PCA3 genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 CDC20, MYBL2, COL10A1, ALOX15 및 ANKRD34B 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from CDC20, MYBL2, COL10A1, ALOX15 and ANKRD34B genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B 및 TRPM8 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B and TRPM8 genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 HDAC9, ETV1, BEX1, ATP1A1, ERG 및 APOD 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from HDAC9, ETV1, BEX1, ATP1A1, ERG and APOD genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1 및 ALOX15B 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1 and ALOX15B genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B 및 COL2A1 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B and COL2A1 genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 NIPAL3, TSPAN19, RFPL1S, CPM, NEFH 및 CEACAM5 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from NIPAL3, TSPAN19, RFPL1S, CPM, NEFH and CEACAM5 genes, but is not limited thereto.
본 발명에서, 각 아형 별 상이한 발현 패턴을 보이는 유전자 세트는 YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 및 CHGA 유전자에서 선택된 어느 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the gene set showing a different expression pattern for each subtype may include any one or more selected from YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 and CHGA genes, but is not limited thereto.
본 발명의 일 예시에서, 상기 루미널 A(luminal A) 및 상기 루미널 S(luminal S) 아형 중 적어도 하나는 상기 AVPC-I 아형 및 상기 AVPC-M 아형 중 적어도 하나에 비하여 ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B 및 PCA3로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In an example of the present invention, at least one of the luminal A and the luminal S subtype is ANPEP, RLN1, PCAT4 compared to at least one of the AVPC-I subtype and the AVPC-M subtype , PCGEM1, ALOX15B, and one or more genes selected from the group consisting of PCA3 may be expressed at a higher level.
본 발명의 다른 예시에서, 상기 AVPC-I 아형 및 상기 AVPC-M 아형 중 적어도 하나는 상기 루미널 A(luminal A) 및 상기 루미널 S(luminal S) 아형 중 적어도 하나에 비하여 CDC20, MYBL2, COL10A1, ALOX15 및 ANKRD34B로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다. In another example of the present invention, at least one of the AVPC-I subtype and the AVPC-M subtype is CDC20, MYBL2, COL10A1 compared to at least one of the luminal A and luminal S subtypes , one or more genes selected from the group consisting of ALOX15 and ANKRD34B may be expressed at a higher level.
본 발명의 또 다른 예시에서, 상기 루미널 A(luminal A) 아형은 상기 AVPC-I 아형에 비하여 KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B 및 TRPM8로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In another example of the present invention, the luminal A subtype has a higher level of one or more genes selected from the group consisting of KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B and TRPM8 compared to the AVPC-I subtype. level can be expressed.
본 발명의 또 다른 예시에서, 상기 AVPC-I 아형은 상기 루미널 A(luminal A) 아형에 비하여 HDAC9, ETV1, BEX1, ATP1A1, ERG 및 APOD로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In another example of the present invention, the AVPC-I subtype has a higher level of one or more genes selected from the group consisting of HDAC9, ETV1, BEX1, ATP1A1, ERG and APOD compared to the luminal A subtype. can be expressed.
본 발명의 또 다른 예시에서, 상기 루미널 A(luminal A) 아형은 상기 루미널 S(luminal S) 아형에 비하여 TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1 및 ALOX15B로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In another example of the present invention, the luminal A subtype is one selected from the group consisting of TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1 and ALOX15B compared to the luminal S subtype. More than one species of genes may be expressed at higher levels.
본 발명의 또 다른 예시에서, 상기 루미널 S(luminal S) 아형은 상기 루미널 A(luminal A) 아형에 비하여 ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B 및 COL2A1로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In another example of the present invention, the luminal S subtype is at least one selected from the group consisting of ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B and COL2A1 compared to the luminal A subtype. Genes can be expressed at higher levels.
본 발명의 또 다른 예시에서, 상기 AVPC-I 아형은 상기 AVPC-M 아형에 비하여 NIPAL3, TSPAN19, RFPL1S, CPM, NEFH 및 CEACAM5로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In another example of the present invention, in the AVPC-I subtype, one or more genes selected from the group consisting of NIPAL3, TSPAN19, RFPL1S, CPM, NEFH and CEACAM5 may be expressed at a higher level than the AVPC-M subtype. .
본 발명의 또 다른 예시에서, 상기 AVPC-M 아형은 상기 AVPC-I 아형에 비하여 YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 및 CHGA로 이루어진 군에서 선택된 1종 이상의 유전자가 더 높은 수준으로 발현될 수 있다.In another example of the present invention, the AVPC-M subtype has a higher level of one or more genes selected from the group consisting of YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 and CHGA compared to the AVPC-I subtype. can be expressed.
본 발명의 연산부에서 분류된 상기 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형 각각은 상기 아형을 가진 목적하는 개체로부터 분리된 생물학적 시료, 바람직하게는 혈청 내 PAP 단백질의 발현 수준에 대한 PSA 단백질의 발현 수준의 비율(PSA/PAP)이 서로 동일하거나 상이할 수 있다.Each of the luminal A subtypes, luminal S subtypes, AVPC-I subtypes and AVPC-M subtypes classified by the operation unit of the present invention is a biological sample isolated from a target subject having the subtype, preferably PAP protein in serum. The ratio of the expression level of the PSA protein to the expression level (PSA/PAP) may be the same or different from each other.
본 발명의 일 예시에서, 루미널 A 아형은 상기 루미널 A 아형을 가진 목적하는 개체로부터 분리된 생물학적 시료, 바람직하게는 혈청 내 PAP 단백질의 발현 수준에 대한 PSA 단백질의 발현 수준의 비율(PSA/PAP)이 20 초과의 값일 수 있으나, 이에 제한되는 것은 아니다.In one example of the present invention, the luminal A subtype is the ratio of the expression level of PSA protein to the expression level of PAP protein in a biological sample, preferably serum, isolated from a subject having the luminal A subtype (PSA/ PAP) may be a value greater than 20, but is not limited thereto.
본 발명의 다른 예시에서, 루미널 S 아형은 상기 루미널 S 아형을 가진 목적하는 개체로부터 분리된 생물학적 시료, 바람직하게는 혈청 내 PAP 단백질의 발현 수준에 대한 PSA 단백질의 발현 수준의 비율(PSA/PAP)이 20 이하의 값일 수 있으나, 이에 제한되는 것은 아니다.In another example of the present invention, the luminal S subtype is the ratio of the expression level of PSA protein to the expression level of PAP protein in a biological sample, preferably serum, isolated from a subject having the luminal S subtype (PSA/ PAP) may be a value of 20 or less, but is not limited thereto.
본 발명의 또 다른 예시에서, AVPC-I 아형은 상기 AVPC-I 아형을 가진 목적하는 개체로부터 분리된 생물학적 시료, 바람직하게는 혈청 내 PAP 단백질의 발현 수준에 대한 PSA 단백질의 발현 수준의 비율(PSA/PAP)이 20 이하의 값일 수 있으나, 이에 제한되는 것은 아니다.In another example of the present invention, the AVPC-I subtype is the ratio of the expression level of PSA protein to the expression level of PAP protein in a biological sample, preferably serum, isolated from a target subject having the AVPC-I subtype (PSA). /PAP) may be a value of 20 or less, but is not limited thereto.
본 발명의 또 다른 예시에서, AVPC-M 아형은 상기 AVPC-M 아형을 가진 목적하는 개체로부터 분리된 생물학적 시료, 바람직하게는 혈청 내 PAP 단백질의 발현 수준에 대한 PSA 단백질의 발현 수준의 비율(PSA/PAP)이 20 초과의 값일 수 있으나, 이에 제한되는 것은 아니다.In another example of the present invention, the AVPC-M subtype is the ratio of the expression level of PSA protein to the expression level of PAP protein in a biological sample, preferably serum, isolated from a subject having said AVPC-M subtype (PSA). /PAP) may be a value greater than 20, but is not limited thereto.
본 발명에서 상기 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형은 각각 항암제에 대하여 상이한 감수성을 보일 수 있다. In the present invention, the luminal subtype A, luminal S subtype, AVPC-I subtype, and AVPC-M subtype may show different sensitivities to anticancer agents, respectively.
본 발명에서 각 아형 별 상이한 감수성을 보이는 항암제로는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 소라페닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 데시타빈, 카페시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 아나스트로졸, 레트로졸, 보로졸, 로무스틴, 보리노스텟, 엔티노스텟, 카르무스틴, 안드로겐 억제제 및 도세탁셀에서 선택된 어느 하나 이상인 것일 수 있고, 바람직하게는 도세탁셀(docetaxel) 또는 안드로겐 억제제(androgen inhibitor)일 수 있으나, 이에 제한되는 것은 아니다. 여기서, 상기 안드로겐 억제제는 비칼루타미드, 플루타미드, 칼루스테론, 드로모스타놀론,프로피오네이트, 에피티오스타놀, 고세렐린, 류프롤리드, 메피티오스탄, 닐루타미드, 테스토락톤 및 트리로스탄으로 이루어진 군으로부터 선택되는 적어도 하나인 것일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, anticancer agents showing different sensitivities for each subtype include nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosu Tinib, axitinib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, viscumalbum, aspart Laginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tusetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine , alprostadil, holmium nitrate chitosan, gemcitabine, doxyfluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, fluoro Uracil, fludagabine, enocitabine, decitabine, capecitabine, mercaptopurine, thioguanine, cladribine, carmofer, raltitrexed, irinotecan, belotecan, topotecan, vinorelbine, etoposide, Vincristine, Vinblastine, Teniposide, Doxorubicin, Idarubicin, Epirubicin, Mitoxantrone, Mitomycin, Bleromycin, Daunorubicin, Dactinomycin, Pyrarubicin, Aclarubicin, Pep Romaycin, temsirolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melparan, altretmine, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, Tretonin, exemestane, aminoglutethimide, anagrelide, nabelbine, fadrazole, tamoxifen, toremifene, anastrozole, letrozole, vorozole, lomustine, vorinostat, entinostat , may be any one or more selected from carmustine, androgen inhibitors and docetaxel, preferably docetaxel (docetaxel) or androgen inhibitors (androgen inhibitor), but is not limited thereto. Here, the androgen inhibitor is bicalutamide, flutamide, calusterone, dromostanolone, propionate, epithiostanol, goserelin, leuprolide, mepitiostan, nilutamide, testolactone and tri It may be at least one selected from the group consisting of rostan, but is not limited thereto.
본 발명의 일 예시에서 상기 루미널 A 아형은 도세탁셀(docetaxel)에 내성을 가지며, 안드로겐 억제제(androgen inhibitor)에 감수성을 가지는 것일 수 있다.In an example of the present invention, the luminal A subtype may have resistance to docetaxel and sensitivity to androgen inhibitors.
본 발명의 다른 예시에서 상기 루미널 S 아형은 도세탁셀에 감수성을 가지며, 안드로겐 억제제에 감수성을 가지는 것일 수 있다.In another example of the present invention, the luminal S subtype may be sensitive to docetaxel and sensitive to androgen inhibitors.
본 발명의 또 다른 예시에서 상기 AVPC-I 아형은 도세탁셀에 감수성을 가지며, 안드로겐 억제제에 내성을 가지는 것일 수 있다.In another example of the present invention, the AVPC-I subtype may be sensitive to docetaxel and resistant to androgen inhibitors.
본 발명의 또 다른 예시에서 AVPC-M 아형은 도세탁셀에 내성을 가지며, 안드로겐 억제제에 내성을 가지는 것일 수 있다.In another example of the present invention, the AVPC-M subtype may be resistant to docetaxel and resistant to androgen inhibitors.
본 발명의 아형 분류 장치에서, 목적하는 개체, 생물학적 시료 및 돌연변이의 정의는 상기 아형 분류 방법에서 기재된 바와 중복되어 이하 명세서의 과도한 복잡을 피하고자 그 기재를 생략한다. In the subtyping apparatus of the present invention, the definitions of the subject, biological sample and mutation overlap with those described in the subtyping method, and description thereof is omitted to avoid excessive complexity of the following specification.
본 발명에서는 암, 특히는 전립선암을 4가지 아형으로 분류하는 방법을 제공함에 따라, 각 아형 별 항암제 치료 반응성 또는 예후 예측이 가능하며, 이를 활용하여 목적하는 개체에서 발병한 전립선암의 아형을 분류한 뒤 적절한 치료 또는 모니터링 계획을 세울 수 있는 이점을 얻을 수 있다.As the present invention provides a method for classifying cancer, particularly prostate cancer, into four subtypes, it is possible to predict anticancer drug treatment reactivity or prognosis for each subtype. This can benefit from the ability to develop an appropriate treatment or monitoring plan.
도 1은 본 발명의 준비예 7에 따른, 전립선암 유전자 맵을 나타낸 것이다.
도 2는 본 발명의 준비예 8에 따른, TCGA 데이터 세트의 각 클러스터의 비율 추정(proportion estimate; PE)을 계산한 것이다.
도 3은 본 발명의 실험예 1에 따른, 각 클러스터의 게놈 특성을 분석한 것이다.
도 4는 본 발명의 실험예 1에 따른, 각 클러스터의 게놈 특성을 분석한 것이다.
도 5는 본 발명의 실험예 2에 따른, 각 클러스터의 게놈 특성을 분석한 것이다.
도 6은 본 발명의 실험예 3에 따른 클러스터간의 특성을 비교한 결과를 나타낸 것이다.
도 7은 본 발명의 실험예 4에 따른, 각 클러스터의 mRNA 특성을 확인한 것이다.
도 8은 본 발명의 실험예 5에 따른, 각 클러스터의 병리학적 특성을 확인한 것이다.
도 9는 본 발명의 실험예 6에 따른, 각 클러스터 별 도세탁셀에 대한 민감도를 테스트한 것이다.
도 10은 본 발명의 실험예 7에 따른, PSA/PAP 비율에 따른 도세탁셀 및 파클리탁셀에 대한 민감도를 테스트한 것이다.
도 11은 본 발명의 실험예 7에 따른, PSA/PAP 비율에 따른 전립선암의 예후를 테스트한 것이다.
도 12는 본 발명의 실험예 9에 따른, TCGA 데이터 세트에서 각 전립선암 아형의 유전자의 발현 차이를 계산한 것이다.
도 13은 본 발명의 실험예 10에 따른, TCGA 데이터 세트에서 각 전립선암 아형의 유전자의 발현 차이를 계산한 것이다.
도 14는 본 발명의 실험예 11에 따른, TCGA 데이터 세트에서 각 전립선암 아형의 유전자의 발현 차이를 계산한 것이다.
도 15는 본 발명의 실험예 12에 따른, TCGA 데이터 세트에서 각 전립선암 아형의 유전자의 발현 차이를 계산한 것이다.1 shows a prostate cancer gene map according to Preparation Example 7 of the present invention.
2 is a calculation of a proportion estimate (PE) of each cluster of a TCGA data set according to Preparation Example 8 of the present invention.
3 is an analysis of the genomic characteristics of each cluster according to Experimental Example 1 of the present invention.
4 is an analysis of the genomic characteristics of each cluster according to Experimental Example 1 of the present invention.
5 is an analysis of the genomic characteristics of each cluster according to Experimental Example 2 of the present invention.
6 shows a result of comparing characteristics between clusters according to Experimental Example 3 of the present invention.
7 shows the mRNA characteristics of each cluster according to Experimental Example 4 of the present invention.
8 shows pathological characteristics of each cluster according to Experimental Example 5 of the present invention.
9 is a test for sensitivity to docetaxel for each cluster, according to Experimental Example 6 of the present invention.
10 is a test for sensitivity to docetaxel and paclitaxel according to the PSA / PAP ratio according to Experimental Example 7 of the present invention.
11 is a test for prognosis of prostate cancer according to the PSA/PAP ratio according to Experimental Example 7 of the present invention.
12 is a graph showing the calculation of differences in the expression of genes of each prostate cancer subtype in the TCGA data set according to Experimental Example 9 of the present invention.
13 is a graph showing the calculation of differences in the expression of genes of each prostate cancer subtype in the TCGA data set according to Experimental Example 10 of the present invention.
14 is a graph showing the calculation of differences in the expression of genes of each prostate cancer subtype in the TCGA data set according to Experimental Example 11 of the present invention.
15 is a graph showing the calculation of differences in the expression of genes of each prostate cancer subtype in the TCGA data set according to Experimental Example 12 of the present invention.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당 업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example
[준비예 1] 연구 설계[Preparation Example 1] Study design
공개적으로 사용 가능한 벌크 및 단일 세포 RNA 서열 분석 데이터를 분석하여 전립선 상피 세포에서 발현되는 1,629 개의 유전자를 정의했다. 컨센서스 클러스터링과 CIBERSORT 디컨볼루션은 클래스 발견 및 비율 추정 분석에 사용되었다. 암 게놈 아틀라스 전립선암(TCGA-PRAD) 데이터 세트는 훈련 세트로 사용되었다. 결과 클러스터는 임상, 병리 및 게놈 특성과 생존에 미치는 영향과 관련하여 분석되었다.Publicly available bulk and single-cell RNA sequencing data were analyzed to define 1,629 genes expressed in prostate epithelial cells. Consensus clustering and CIBERSORT deconvolution were used for class discovery and ratio estimation analysis. The Cancer Genome Atlas Prostate Cancer (TCGA-PRAD) data set was used as the training set. Outcome clusters were analyzed for clinical, pathological and genomic characteristics and their impact on survival.
[준비예 2] 단일세포 및 다량 RNA 서열 데이터에서 전립선 상피 발현 유전자 식별[Preparation Example 2] Identification of prostate epithelial expression genes from single cell and large-scale RNA sequence data
전립선암과 관련된 유전자 식별을 위하여, 단일세포 및 다량 RNA 서열 데이터를 분석하였다. 먼저 Henry et al(doi: 10.1016/j.celrep.2018.11.086)의 3개의 인간 전립선 표본에서 단일 세포 RNA 서열 데이터를 사용하였다. 상기 데이터의 매핑 된 읽기 수 데이터는 GEO(GSE117403)에서 다운로드하고 10X Genomics Cell Ranger 집계 함수를 사용하여 집계했다. 분석 파이프 라인은 Henry et al(doi: 10.1016/j.celrep.2018.11.086)을 따랐고, 내강, 기저, 곤봉형, 언덕형 및 신경 내분비 전립선 상피 세포에 대한 차등 발현 유전자(differentially expressed gene; DEG) 목록을 복제했다. 다음으로, 동일한 방법으로 유세포분석을 통해 인간 전립선암에 대하여 다량의 RNA 서열 데이터를 분석하였다. GEO(GSE117271)에서 기저, 내강 및 기타 상피 기질의 킬로베이스 백만 당 단편(FPKM) 값을 다운로드한 뒤, 모든 상피 조직 또는 나머지에 비해 상피 하위 집단에서 5배 이상 과발현 된 유전자를 선택하였다. 이후 상기 단일세포 및 다량 세포 데이터 세트에 대한 DEG 목록을 병합하고 Entrez 유전자 ID에 매핑하였다.For the identification of genes associated with prostate cancer, single-cell and large-scale RNA sequence data were analyzed. First, we used single-cell RNA sequence data from three human prostate specimens from Henry et al (doi: 10.1016/j.celrep.2018.11.086). The mapped read count data of the above data were downloaded from GEO (GSE117403) and aggregated using the 10X Genomics Cell Ranger aggregation function. The analysis pipeline followed Henry et al (doi: 10.1016/j.celrep.2018.11.086) and differentially expressed genes (DEG) for luminal, basal, club-shaped, hill-shaped and neuroendocrine prostate epithelial cells. The list was duplicated. Next, a large amount of RNA sequence data was analyzed for human prostate cancer through flow cytometry in the same manner. After downloading fragments per kilobase (FPKM) values of basal, luminal and other epithelial matrix from GEO (GSE117271), genes that were overexpressed at least 5-fold in all epithelial tissues or epithelial subpopulations relative to the rest were selected. DEG lists for the single-cell and multi-cell data sets were then merged and mapped to Entrez gene IDs.
[준비예 3] RNA 서열 데이터 수집을 위한 컨센서스 클러스터링[Preparation Example 3] Consensus clustering for RNA sequence data collection
유전자의 발현 배열 데이터의 클래스 발견 및 시각화를 위하여 리샘플링 기반 방법인 컨센서스 클러스터링을 수행하였다. UCSC Xena 브라우저에서 주석이 달린 TCGA-PRAD(The Cancer Genome Atlas Prostate Adenocarcinoma) 유전자의 발현, 임상 및 게놈 데이터를 다운로드했다. 550개 샘플의 mRNA 발현 수준을 포함하는 기대 최대화에 의한 RNA-Seq(RSEM) 데이터를 도출하였다. 데이터 도출에는 컨센서스 클러스터링 모듈 버전 7.2를 사용했으며 매개 변수는 다음과 같다. Kmax = 15; 리샘플링 반복 = 20; 클러스터링 알고리즘 = 자체 구성 맵; 클러스터 기준 = 열; 거리 측정 = 유클리드; resample = 0.80 비율의 서브 샘플; 병합 유형 = 평균; 하강 반복 = 2,000; 정규화 type = row-wise; 정규화 반복 = 0. cBioPortal의 TCGA-PRAD 데이터 세트에서 미리 계산된 DNA 순도(ABSOLUTE, CLONET) 및 RNA 순도(ISOpure, DeMix 순도) 점수, AR 활성 점수, AR mRNA 및 단백질 발현을 사용했다. TCGA 전체 암 아틀라스의 생존 데이터도 cBioPortal에서 다운로드했다.Consensus clustering, a resampling-based method, was performed for class discovery and visualization of gene expression sequence data. Expression, clinical and genomic data of the annotated TCGA-PRAD (The Cancer Genome Atlas Prostate Adenocarcinoma) gene were downloaded from the UCSC Xena browser. RNA-Seq (RSEM) data by expected maximization including mRNA expression levels of 550 samples were derived. Consensus clustering module version 7.2 was used for data derivation, and the parameters are as follows. Kmax = 15; resampling iterations = 20; clustering algorithm = self-organizing map; by cluster = column; Measure distance = Euclid; resample = subsample with a rate of 0.80; merge type = average; Falling iterations = 2,000; normalization type = row-wise; Normalized repeats = 0. Pre-calculated DNA purity (ABSOLUTE, CLONET) and RNA purity (ISOpure, DeMix purity) scores, AR activity scores, AR mRNA and protein expression from cBioPortal's TCGA-PRAD data set were used. Survival data from the TCGA Whole Cancer Atlas was also downloaded from cBioPortal.
[준비예 4] RNA 서열 데이터 역필터링 및 정규화[Preparation Example 4] Inverse filtering and normalization of RNA sequence data
다음으로 대량 mRNA 서열 데이터를 기반으로 이종 조직의 역필터링(deconvolution)을 위한 디지털 세포 측정 도구인 CIBERSORT를 사용했다. 상기 CIBERSORT는 선형 지원 벡터 회귀 모델을 기반으로 하는데, 상기 모델은 모든 세포 유형에서 순수 조직 또는 세포 유형에 따른 상대적인 가중치를 부여하는 것이다. Entrez 유전자 ID 및 HUGO 유전자-기호 주석이 있는 RNA 서열이 판독 및 정규화되어 혼합 파일에 로드되었다. 상기 발현 값들은 각각 TCGA, CPC-GENE 및 DKFZ 및 SU2C-PCF 데이터 세트에 대한 RSEM, RPKM 및 FPKM과 같은 상대값이다. 유전자의 특징은 컨센서스 클러스터링에 의해 미리 결정된 TCGA-PRAD 데이터 세트 클러스터에서 전립선 상피 발현 유전자의 평균 유전자의 발현 값으로 정의되었다.Next, we used CIBERSORT, a digital cytometry tool for deconvolution of heterogeneous tissues based on bulk mRNA sequence data. The CIBERSORT is based on a linear support vector regression model, which assigns relative weights according to naive tissue or cell types in all cell types. Entrez gene ID and HUGO gene-symbol annotated RNA sequences were read and normalized and loaded into a mixed file. The expression values are relative values such as RSEM, RPKM and FPKM for the TCGA, CPC-GENE and DKFZ and SU2C-PCF data sets, respectively. Characteristics of genes were defined as average gene expression values of prostate epithelial-expressed genes in the TCGA-PRAD data set clusters predetermined by consensus clustering.
[준비예 5] in silico에서 도세탁셀 및 파클리탁셀에 대한 감수성 분석[Preparation Example 5] Sensitivity analysis for docetaxel and paclitaxel in silico
전립선암 환자에서 도세탁셀 감수성을 예측하기 위하여, 도세탁셀 요법에 대한 유방 종양 반응과 관련된 이전 유전자의 발현 특징을 사용하였다. 여기서 도세탁셀 감수성은 종양 크기 감소 정도에 의해 평가되었다. 도세탁셀에 반응한 환자에서 과발현(n=13) 및 과소 발현(n=43)된 유전자 세트를 사용하여 GenePattern 플랫폼에 모듈로 로드된 단일 샘플 유전자 세트 농축 분석(ssGSEA)을 실행했다. 도세탁셀에 반응한 환자의 점수는 과발현 된 유전자에서 과소 발현된 유전자의 ssGSEA 점수를 빼서 계산하였다. 파클리탁셀 민감도를 예측하기 위해 암 치료제 반응 포털(CTRP v2, http://portal.broadinstitute.org/ctrp.v2.1)에서 유전자의 발현과 파클리탁셀에 감수성이 있는 암 세포주 간 상대적인 양의 상관 관계(Pearson r> 0.3)를 보이는 유전자를 선택했다(1- 곡선 아래 영역 값). 모든 점수 값은 z 점수 정규화를 거쳤다.To predict docetaxel sensitivity in prostate cancer patients, we used the expression characteristics of previous genes associated with breast tumor response to docetaxel therapy. Here, docetaxel sensitivity was assessed by the extent of tumor size reduction. A single-sample gene set enrichment assay (ssGSEA) was performed, loaded as a module into the GenePattern platform, using overexpressed (n=13) and underexpressed (n=43) gene sets in patients responding to docetaxel. The scores of patients responding to docetaxel were calculated by subtracting the ssGSEA score of the underexpressed gene from the overexpressed gene. To predict paclitaxel sensitivity, a relative positive correlation between gene expression in the Cancer Therapeutic Response Portal (CTRP v2, http://portal.broadinstitute.org/ctrp.v2.1) and a cancer cell line susceptible to paclitaxel (Pearson) r>0.3) were selected (1-value of the area under the curve). All score values were subjected to z-score normalization.
[준비예 6] 환자 데이터베이스에서 도세탁셀 감수성 분석[Preparation Example 6] Docetaxel sensitivity analysis in the patient database
전이성 거세 저항성 전립선 암(mCRPC) 환자에 대한 데이터를 분석하였다. 구체적으로 상기 환자는 1) 도세탁셀-프레디손 화학 요법을 3회 이상 연속으로 받았으며, 2) 복부 골반 CT 및 전신 뼈 스캔 영상을 화학요법 전, 화학요법 중, 화학요법 후 촬영하여 평가하였으며, 3) 초기 화학 요법 시작일 전 30 일 이내에 혈청 PSA 및 PAP 테스트 결과를 획득했다. 도세탁셀 반응은 RECIST 1.1 기준을 사용하여 측정되었다.Data for patients with metastatic castration-resistant prostate cancer (mCRPC) were analyzed. Specifically, the patient 1) received docetaxel-
다음으로 GraphPad Prism 버전 8.4.3(GraphPad, San Diego, CA, USA)을 사용하여 통계 분석을 수행했다. P-값은 달리 명시되지 않는 한 생존 곡선 비교를 위해 로그 순위(Mantel-Cox) 테스트를 사용하여 추정되었다. 약물 민감도 점수와 아형 PE 간의 상관 관계 분석을 위해 Spearman r 값과 양측 P-값이 보고되었다. 다중 비교를 위해 ANOVA 및 Kruskal-Wallis 테스트가 사용되었다.Statistical analysis was then performed using GraphPad Prism version 8.4.3 (GraphPad, San Diego, CA, USA). P-values were estimated using the log rank (Mantel-Cox) test for survival curve comparisons unless otherwise specified. Spearman r values and bilateral P-values were reported for correlation analysis between drug sensitivity scores and subtype PE. ANOVA and Kruskal-Wallis tests were used for multiple comparisons.
[준비예 7] 전립선 상피 세포 발현 유전자를 4개의 클러스터로 분류[Preparation Example 7] Classification of prostate epithelial cell expression genes into four clusters
인간 전립선 조직 샘플의 다량 RNA 서열 데이터에서 DEG 목록을 추출한 후, 샘플의 다른 모든 세포 유형과 비교할때 상피 세포 집단에 의해 발현되는 유전자를 식별하여, 하기 표 2와 같이 나타내었다. After extracting the DEG list from the large amount of RNA sequence data of human prostate tissue samples, the genes expressed by the epithelial cell population when compared to all other cell types in the sample were identified, and are shown in Table 2 below.
또한, 단일 RNA 서열 데이터에서 DEG 목록을 추출한 후, 샘플의 다른 모든 세포 유형과 비교할 때 상피 세포 집단에 의해 발현되는 유전자를 식별하여, 하기 표 3과 같이 나타내었다.In addition, after extracting the DEG list from the single RNA sequence data, the genes expressed by the epithelial cell population were identified when compared to all other cell types in the sample, and are shown in Table 3 below.
상기 표 2 및 3에 따라 1,629 개의 유전자를 식별한 후 유전자 ID 또는 기호가 불일치하는 24개를 제거한 1,593개 유전자를 사용하는 TCGA-PRAD 데이터 세트의 초기 맵 클러스터링을 도 1에 나타내었다.The initial map clustering of the TCGA-PRAD data set using 1,593 genes from which 24 inconsistent gene IDs or symbols were removed after 1,629 genes were identified according to Tables 2 and 3 above is shown in FIG. 1 .
상기 도 1에서의 클러스터는 모집단이 명확하게 분리될 수 없음을 확인하였다. 따라서 다음으로 표 4에서와 같이 사용 가능한 순도 데이터 275개를 확보하였고, 그 중 DNA 순도(ABSOLUTE, CLONET 순도 값> 0.5) 및 RNA 순도(ISOpure, DeMix 순도 값> 0.5)로 샘플을 필터링하여 138 개를 선택할 수 있었다.The cluster in FIG. 1 confirmed that the population could not be clearly separated. Therefore, 275 usable purity data were obtained as shown in Table 4, and among them, 138 samples were filtered by DNA purity (ABSOLUTE, CLONET purity value > 0.5) and RNA purity (ISOpure, DeMix purity value > 0.5). could choose
[준비예 8] 역필터링 분석에 의해 할당된 클러스터 분석[Preparation Example 8] Cluster analysis assigned by inverse filtering analysis
역필터링 분석에 의해 할당된 클러스터의 게놈 특성을 분석하였다. CIBERSORT 역필터링 분석 (P<0.05)을 실행하여 4개의 클러스터 중 1,271개를 포함하는 유전자 특성을 생성하고 TCGA 데이터 세트의 각 클러스터의 비율 추정(PE)을 계산하여 도 2 및 하기 표 5와 같이 나타내었다.The genomic characteristics of the assigned clusters were analyzed by inverse filtering analysis. CIBERSORT inverse filtering analysis (P<0.05) was performed to generate genetic traits containing 1,271 out of 4 clusters, and the proportion estimate (PE) of each cluster in the TCGA data set was calculated, as shown in Figure 2 and Table 5 below. It was.
도 2 및 상기 표 5에 나타난 것처럼 클러스터 PE가> 0.5 일 때 샘플이 각 클러스터에 할당되었고 최대 PE≤0.5 인 샘플은 "혼합"으로 지정되었다. 상기 정의에 따라 샘플은 클러스터로 분류되었다. 각 클러스터의 비율은 클러스터 A(n = 163, 30.0 %), 클러스터 B(n = 141, 26.0 %), 클러스터 C(n = 80, 14.7 %), 클러스터 D(n = 23, 4.2 %)와 같이 나타났고, 나머지는 혼합(n = 136, 25.0 %)으로 지정되었다. As shown in Figure 2 and Table 5 above, samples were assigned to each cluster when cluster PE > 0.5 and samples with maximum PE ≤ 0.5 were designated as “mixed”. According to the definition above, the samples were classified into clusters. The proportion of each cluster is as follows: Cluster A (n = 163, 30.0%), Cluster B (n = 141, 26.0%), Cluster C (n = 80, 14.7%), Cluster D (n = 23, 4.2%) appeared, and the remainder was designated as mixed (n = 136, 25.0 %).
[실험예 1] 할당된 클러스터의 게놈 특성 분석(1)[Experimental Example 1] Analysis of genomic characteristics of the assigned cluster (1)
상기 준비예 7의 역필터링 분석에 의해 할당된 클러스터의 게놈 특성을 분석하였다. 구체적으로 cBioPortal의 그룹 비교 기능을 사용하여 클러스터 A 내지 D의 게놈 특성을 분석하여 도 3에 나타내었다. The genomic characteristics of the assigned clusters were analyzed by the inverse filtering analysis of Preparation Example 7. Specifically, the genomic characteristics of clusters A to D were analyzed using the group comparison function of cBioPortal and shown in FIG. 3 .
도 3에 나타난 바와 같이, 클러스터 A에서는 SPOP 돌연변이 및 PRDM1 결실; 클러스터 B에서는 PTEN 결실; 클러스터 C에서는 TP53 돌연변이 및 PTEN 결실; 및 클러스터 D에서는 TP53 돌연변이, PIK3CA 돌연변이, PTEN 결실, PRDM1 결실 및 PTK2 결실;이 나타난 것을 확인하였다.As shown in Fig. 3, in cluster A, SPOP mutation and PRDM1 deletion; PTEN deletion in cluster B; In cluster C, TP53 mutation and PTEN deletion; and cluster D, TP53 mutation, PIK3CA mutation, PTEN deletion, PRDM1 deletion and PTK2 deletion; were confirmed.
[실험예 2] 할당된 클러스터의 게놈 특성 분석(2)[Experimental Example 2] Analysis of genomic characteristics of assigned clusters (2)
상기 준비예 7의 역필터링 분석에 의해 할당된 클러스터의 게놈 특성을 분석하였다. 구체적으로 cBioPortal의 그룹 비교 기능을 사용하여 클러스터 A 내지 D의 게놈 특성을 분석하여 도 4 및 도 5에 나타내었다. The genomic characteristics of the assigned clusters were analyzed by the inverse filtering analysis of Preparation Example 7. Specifically, the genomic characteristics of clusters A to D were analyzed using the group comparison function of cBioPortal and shown in FIGS. 4 and 5 .
도 4에 나타난 바와 같이, 클러스터 B 및 D에서 ETS-패밀리 융합(ERG; ETV1, 4, 5 또는 6) 빈도가 높은 것을 확인하였고, 도 5에 나타난 바와 같이, 클러스터 A에서 SPOP 돌연변이 빈도가 높은 것을 확인하였다.As shown in Figure 4, it was confirmed that the frequency of ETS-family fusion (ERG; ETV1, 4, 5 or 6) in clusters B and D was high, and as shown in Figure 5, the frequency of SPOP mutation in cluster A was high Confirmed.
[실험예 3] 클러스터에 따른 전사체적 특성 분석[Experimental Example 3] Analysis of transcriptional characteristics according to clusters
홀마크 50-유전자 세트를 사용하여 각 클러스터를 다른 클러스터와 비교하는 GSEA를 수행하여 도 6에 나타내었다.GSEA was performed to compare each cluster with other clusters using the Hallmark 50-gene set and is shown in FIG. 6 .
상기 도 6에 나타난 것처럼, 클러스터 A는 MYC_TARGETS, DNA_REPAIR 및 OXIDATIVE_PHOSPHORYLATION에서 강화되었다. 클러스터 B는 TGF_BETA_SIGNALING, ANDROGEN_RESPONSE 및 PROTEIN_SECRETION에서 보강되었다. 클러스터 C는 E2F_TARGETS, MTORC1_SIGNALING 및 INTERFERON 응답으로 강화되었다. 클러스터 D는 해당작용(GLYCOLYSIS) 및 에스트로겐(ESTROGEN) 반응이 풍부했다.6, cluster A was enriched in MYC_TARGETS, DNA_REPAIR and OXIDATIVE_PHOSPHORYLATION. Cluster B is augmented with TGF_BETA_SIGNALING, ANDROGEN_RESPONSE and PROTEIN_SECRETION. Cluster C is hardened with E2F_TARGETS, MTORC1_SIGNALING and INTERFERON responses. Cluster D was rich in GLYCOLYSIS and ESTROGEN responses.
[실험예 4] 클러스터에 따른 안드로겐 수용체 활동 분석[Experimental Example 4] Androgen receptor activity analysis according to clusters
클러스터에 따른 안드로겐 수용체(AR) 활동을 분석하기 위하여, TCGA-PRAD 데이터에서 4 개 클러스터의 게놈 및 전사체인 mRNA 특성을 확인하여, 도 7에 나타내었다. In order to analyze the androgen receptor (AR) activity according to the clusters, the genomic and transcript mRNA characteristics of four clusters were confirmed in the TCGA-PRAD data, and are shown in FIG. 7 .
도 7에 나타난 것처럼, 안드로겐 수용체(AR)의 활성 점수는 클러스터 A에서 높았고, 안드로겐 mRNA 발현 수준은 클러스터 A 및 D에서 낮았으며, 안드로겐 단백질 발현 수준은 모든 클러스터에서 비슷한 수준으로 유지된 바, 클러스터 A 및 D에서 안드로겐 수용체 억제제에 대한 내성이 있을 것으로 예측되었다.As shown in FIG. 7 , the activity score of androgen receptor (AR) was high in cluster A, androgen mRNA expression level was low in clusters A and D, and androgen protein expression level was maintained at a similar level in all clusters, cluster A and D, predicted to be resistant to androgen receptor inhibitors.
[실험예 5] 클러스터에 따른 병리학적 특성 분석[Experimental Example 5] Pathological characteristics analysis according to clusters
클러스터 분류에 따른 예후 예측을 확인하기 위하여 분석을 수행하였다. 구체적으로는 카이제곱검정 및 Benjamini-Hochberg 절차로 통계분석 하여 Gleason 점수와 병리학적 TNM 병기 분포를 확인한 결과를 도 8에 나타내었다.Analysis was performed to confirm the prognostic prediction according to cluster classification. Specifically, the results of statistical analysis using the chi-square test and the Benjamini-Hochberg procedure to confirm the Gleason score and the pathological TNM stage distribution are shown in FIG. 8 .
도 8에 나타난 바와 같이, 클러스터 C 및 D는 A 및 B 보다 더 높은 Gleason 점수와 더 진행된 TNM 병기를 특징으로 하는 바, 클러스터 C 및 D에 해당하는 경우 예후가 더 나쁜 것을 확인할 수 있었다. As shown in FIG. 8 , clusters C and D were characterized by a higher Gleason score and more advanced TNM stage than A and B, and it was confirmed that clusters C and D had a worse prognosis.
[실험예 6] In silico에서 도세탁셀 및 파클리탁셀에 대한 민감도 테스트[Experimental Example 6] In silico sensitivity test for docetaxel and paclitaxel
전립선암에서 도세탁셀 및 파클리탁셀에 대한 민감도를 예측하기 위해 In silico에서 스크리닝 테스트를 수행하였다. 클러스터를 구성하는 유전자에 대하여 종양 약물 반응과 양성 또는 음성 상관 관계를 조사하고, 샘플의 약물 반응 또는 민감도 점수는 ssGSEA에 의해 계산한 결과를 하기 표 6 및 도 9에 나타내었다. A screening test was performed in silico to predict the sensitivity to docetaxel and paclitaxel in prostate cancer. A positive or negative correlation with a tumor drug response was investigated with respect to the genes constituting the cluster, and the drug response or sensitivity score of the sample was calculated by ssGSEA, and the results are shown in Tables 6 and 9 below.
감수성paclitaxel
sensibility
발현 증가in docetaxel
increased expression
발현 감소in docetaxel
decreased expression
감수성docetaxel
sensibility
상기 표 6 및 도 9에 나타난 바와 같이, 클러스터 B가 도세탁셀에 감수성이 있음을 확인하였다.As shown in Table 6 and Figure 9, it was confirmed that cluster B is sensitive to docetaxel.
[실험예 7] 혈청 내 PSA/PAP 비율의 도세탁셀 감수성 예측능력 확인[Experimental Example 7] Confirmation of the ability to predict docetaxel sensitivity of PSA / PAP ratio in serum
혈청 PSA/PAP 비율을 측정하여 거세저항성 전립선암 환자(mCRPC)에 대한 도세탁셀 반응성을 확인하였다. 도세탁셀 반응군(SD+PR)과 비 반응군(PD)을 나누어, PSA/PAP 비율을 확인한 결과를 도 10에 나타내었고, 도세탁셀 및 프레드니손을 병용 투여한 경우 PSA/PAP 비율에 따른 전립선암 환자의 생존률을 도 11에 나타내었다.By measuring the serum PSA/PAP ratio, docetaxel reactivity was confirmed for castration-resistant prostate cancer patients (mCRPC). The results of confirming the PSA/PAP ratio by dividing the docetaxel responder group (SD+PR) and the non-responder group (PD) are shown in FIG. The survival rate is shown in FIG. 11 .
도 10에 나타난 바와 같이, 도세탁셀 반응군이 도세탁셀 비 반응군에 비하여 PSA/PAP 비율이 현저하게 낮은 바(14.5 vs. 43.8, P<0.05, Welch'보정한 unpaired t-test), PSA/PAP 비율이 낮을 경우 도세탁셀에 감수성이 있다는 것을 확인하였고, 도 11에 나타난 바와 같이, PSA/PAP 비율이 20을 초과하는 경우, PSA/PAP 비율이 20 이하인 경우에 비해 생존률이 높은 것을 확인하였다.As shown in FIG. 10 , the docetaxel response group had a significantly lower PSA/PAP ratio than the docetaxel non-responder group (14.5 vs. 43.8, P<0.05, Welch' corrected unpaired t-test), PSA/PAP ratio When this is low, it was confirmed that there is a sensitivity to docetaxel, and as shown in FIG. 11 , when the PSA/PAP ratio exceeds 20, it was confirmed that the survival rate was high compared to the case where the PSA/PAP ratio was 20 or less.
[실험예 8] 각 클러스터에 따른 아형 분류[Experimental Example 8] Subtype classification according to each cluster
상기 클러스터 A 내지 D의 특성에 따른 전립선암의 아형을 하기 표 7과 같이 분류하였다.The subtypes of prostate cancer according to the characteristics of the clusters A to D were classified as shown in Table 7 below.
상기 표 7에서 나타난 것처럼, 클러스터 A는 루미널 A(luminal A) 아형으로, 클러스터 A는 루미널 S(luminal S) 아형으로, 클러스터 C는 면역 침윤성/혈관형성을 띄는 공격적인 변이형 전립선암(aggressive variant PCs immune-infiltrative/angiogenic; AVPC-I) 아형으로, 클러스터 D는 MYC 활성을 띄는 공격적인 변이형 전립선암(aggressive variant PCs Myc active; AVPC-M) 아형으로 분류하였다.As shown in Table 7 above, cluster A is a luminal A subtype, cluster A is a luminal S subtype, and cluster C is an aggressive mutant prostate cancer with immune invasive/angiogenesis. As a variant PCs immune-infiltrative/angiogenic; AVPC-I) subtype, cluster D was classified as an aggressive variant PCs Myc active (AVPC-M) subtype with MYC activity.
[실험예 9] 각 전립선암 아형간 유전자의 발현의 차이 확인(1)[Experimental Example 9] Confirmation of differences in gene expression between each prostate cancer subtype (1)
각 전립선암 아형간 유전자의 발현의 차이를 확인하기 위하여 각 전립선암 아형간 유전자의 발현량을 볼케이노 강화 플롯으로 나타낸 결과를 도 12에 나타내었다.In order to confirm the difference in the expression of genes between each subtype of prostate cancer, the results of expressing the expression levels of genes between each subtype of prostate cancer as a volcano enhancement plot are shown in FIG. 12 .
도 12에서 나타난 바와 같이, 상기 루미널 A(luminal A) 및 상기 루미널 S(luminal S) 아형은 상기 AVPC-I 아형 및 상기 AVPC-M 아형에 비하여 ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B 및 PCA3 유전자의 발현이 더 높고, CDC20, MYBL2, COL10A1, ALOX15 및 ANKRD34B 유전자의 발현이 더 낮은 것을 확인하였다.As shown in FIG. 12 , the luminal A and luminal S subtypes were ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B and PCA3 compared to the AVPC-I subtype and the AVPC-M subtype. It was confirmed that the expression of the gene was higher, and the expression of the CDC20, MYBL2, COL10A1, ALOX15 and ANKRD34B genes was lower.
[실험예 10] 각 전립선암 아형간 유전자의 발현의 차이 확인(2)[Experimental Example 10] Confirmation of differences in gene expression between each prostate cancer subtype (2)
각 전립선암 아형간 유전자의 발현의 차이를 확인하기 위하여 각 전립선암 아형간 유전자의 발현량을 볼케이노 강화 플롯으로 나타낸 결과를 도 13에 나타내었다.In order to confirm the difference in the expression of genes between each prostate cancer subtype, the results of expressing the gene expression level between each prostate cancer subtype in a volcano-enhanced plot are shown in FIG. 13 .
도 13에 나타난 바와 같이, 상기 루미널 A(luminal A) 아형은 AVPC-I 아형에 비하여 KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B 및 TRPM8 유전자의 발현이 더 높고, HDAC9, ETV1, BEX1, ATP1A1, ERG 및 APOD 유전자의 발현이 더 낮은 것을 확인하였다.As shown in FIG. 13 , the luminal A subtype has higher expression of KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B and TRPM8 genes, HDAC9, ETV1, BEX1, ATP1A1 than the AVPC-I subtype. , it was confirmed that the expression of ERG and APOD genes was lower.
[실험예 11] 각 전립선암 아형간 유전자의 발현의 차이 확인(3)[Experimental Example 11] Confirmation of difference in expression of genes between subtypes of prostate cancer (3)
각 전립선암 아형간 유전자의 발현의 차이를 확인하기 위하여 각 전립선암 아형간 유전자의 발현량을 볼케이노 강화 플롯으로 나타낸 결과를 도 14에 나타내었다.In order to confirm the difference in the expression of genes between each subtype of prostate cancer, the results of expressing the expression levels of genes between each subtype of prostate cancer as a volcano-enhanced plot are shown in FIG. 14 .
도 14에 나타난 바와 같이, 상기 루미널 A(luminal A) 아형은 상기 루미널 S(luminal S) 아형에 비하여 TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1 및 ALOX15B 유전자의 발현이 더 높고, ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B 및 COL2A1 유전자의 발현이 더 낮은 것을 확인하였다.14 , the luminal A subtype has higher expression of TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1 and ALOX15B genes than the luminal S subtype, It was confirmed that the expression of ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B and COL2A1 genes was lower.
[실험예 12] 각 전립선암 아형간 유전자의 발현의 차이 확인(4)[Experimental Example 12] Confirmation of difference in expression of genes between subtypes of prostate cancer (4)
각 전립선암 아형간 유전자의 발현의 차이를 확인하기 위하여 각 전립선암 아형간 유전자의 발현량을 볼케이노 강화 플롯으로 나타낸 결과를 도 15에 나타내었다.In order to confirm the difference in the expression of genes between each subtype of prostate cancer, the results of expressing the expression levels of genes between each subtype of prostate cancer as a volcano-enhanced plot are shown in FIG. 15 .
도 15에 나타난 바와 같이, 상기 AVPC-I 아형은 상기 AVPC-M 아형에 비하여 NIPAL3, TSPAN19, RFPL1S, CPM, NEFH 및 CEACAM5 유전자의 발현이 더 높고, YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 및 CHGA 유전자의 발현이 더 낮은 것일 수 있다.As shown in FIG. 15 , the AVPC-I subtype has higher expression of NIPAL3, TSPAN19, RFPL1S, CPM, NEFH and CEACAM5 genes than the AVPC-M subtype, and YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2- 1 and the expression of the CHGA gene may be lower.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예 일뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
<110> Industry-Academic Cooperation Foundation, Yonsei University <120> Prostate cancer subtype classification method and classification apparatus <130> PDPB204208 <160> 12 <170> KoPatentIn 3.0 <210> 1 <211> 374 <212> PRT <213> Homo sapiens <400> 1 Met Ser Arg Val Pro Ser Pro Pro Pro Pro Ala Glu Met Ser Ser Gly 1 5 10 15 Pro Val Ala Glu Ser Trp Cys Tyr Thr Gln Ile Lys Val Val Lys Phe 20 25 30 Ser Tyr Met Trp Thr Ile Asn Asn Phe Ser Phe Cys Arg Glu Glu Met 35 40 45 Gly Glu Val Ile Lys Ser Ser Thr Phe Ser Ser Gly Ala Asn Asp Lys 50 55 60 Leu Lys Trp Cys Leu Arg Val Asn Pro Lys Gly Leu Asp Glu Glu Ser 65 70 75 80 Lys Asp Tyr Leu Ser Leu Tyr Leu Leu Leu Val Ser Cys Pro Lys Ser 85 90 95 Glu Val Arg Ala Lys Phe Lys Phe Ser Ile Leu Asn Ala Lys Gly Glu 100 105 110 Glu Thr Lys Ala Met Glu Ser Gln Arg Ala Tyr Arg Phe Val Gln Gly 115 120 125 Lys Asp Trp Gly Phe Lys Lys Phe Ile Arg Arg Asp Phe Leu Leu Asp 130 135 140 Glu Ala Asn Gly Leu Leu Pro Asp Asp Lys Leu Thr Leu Phe Cys Glu 145 150 155 160 Val Ser Val Val Gln Asp Ser Val Asn Ile Ser Gly Gln Asn Thr Met 165 170 175 Asn Met Val Lys Val Pro Glu Cys Arg Leu Ala Asp Glu Leu Gly Gly 180 185 190 Leu Trp Glu Asn Ser Arg Phe Thr Asp Cys Cys Leu Cys Val Ala Gly 195 200 205 Gln Glu Phe Gln Ala His Lys Ala Ile Leu Ala Ala Arg Ser Pro Val 210 215 220 Phe Ser Ala Met Phe Glu His Glu Met Glu Glu Ser Lys Lys Asn Arg 225 230 235 240 Val Glu Ile Asn Asp Val Glu Pro Glu Val Phe Lys Glu Met Met Cys 245 250 255 Phe Ile Tyr Thr Gly Lys Ala Pro Asn Leu Asp Lys Met Ala Asp Asp 260 265 270 Leu Leu Ala Ala Ala Asp Lys Tyr Ala Leu Glu Arg Leu Lys Val Met 275 280 285 Cys Glu Asp Ala Leu Cys Ser Asn Leu Ser Val Glu Asn Ala Ala Glu 290 295 300 Ile Leu Ile Leu Ala Asp Leu His Ser Ala Asp Gln Leu Lys Thr Gln 305 310 315 320 Ala Val Asp Phe Ile Asn Tyr His Ala Ser Asp Val Leu Glu Thr Ser 325 330 335 Gly Trp Lys Ser Met Val Val Ser His Pro His Leu Val Ala Glu Ala 340 345 350 Tyr Arg Ser Leu Ala Ser Ala Gln Cys Pro Phe Leu Gly Pro Pro Arg 355 360 365 Lys Arg Leu Lys Gln Ser 370 <210> 2 <211> 825 <212> PRT <213> Homo sapiens <400> 2 Met Leu Asp Ile Cys Leu Glu Lys Arg Val Gly Thr Thr Leu Ala Ala 1 5 10 15 Pro Lys Cys Asn Ser Ser Thr Val Arg Phe Gln Gly Leu Ala Glu Gly 20 25 30 Thr Lys Gly Thr Met Lys Met Asp Met Glu Asp Ala Asp Met Thr Leu 35 40 45 Trp Thr Glu Ala Glu Phe Glu Glu Lys Cys Thr Tyr Ile Val Asn Asp 50 55 60 His Pro Trp Asp Ser Gly Ala Asp Gly Gly Thr Ser Val Gln Ala Glu 65 70 75 80 Ala Ser Leu Pro Arg Asn Leu Leu Phe Lys Tyr Ala Thr Asn Ser Glu 85 90 95 Glu Val Ile Gly Val Met Ser Lys Glu Tyr Ile Pro Lys Gly Thr Arg 100 105 110 Phe Gly Pro Leu Ile Gly Glu Ile Tyr Thr Asn Asp Thr Val Pro Lys 115 120 125 Asn Ala Asn Arg Lys Tyr Phe Trp Arg Ile Tyr Ser Arg Gly Glu Leu 130 135 140 His His Phe Ile Asp Gly Phe Asn Glu Glu Lys Ser Asn Trp Met Arg 145 150 155 160 Tyr Val Asn Pro Ala His Ser Pro Arg Glu Gln Asn Leu Ala Ala Cys 165 170 175 Gln Asn Gly Met Asn Ile Tyr Phe Tyr Thr Ile Lys Pro Ile Pro Ala 180 185 190 Asn Gln Glu Leu Leu Val Trp Tyr Cys Arg Asp Phe Ala Glu Arg Leu 195 200 205 His Tyr Pro Tyr Pro Gly Glu Leu Thr Met Met Asn Leu Thr Gln Thr 210 215 220 Gln Ser Ser Leu Lys Gln Pro Ser Thr Glu Lys Asn Glu Leu Cys Pro 225 230 235 240 Lys Asn Val Pro Lys Arg Glu Tyr Ser Val Lys Glu Ile Leu Lys Leu 245 250 255 Asp Ser Asn Pro Ser Lys Gly Lys Asp Leu Tyr Arg Ser Asn Ile Ser 260 265 270 Pro Leu Thr Ser Glu Lys Asp Leu Asp Asp Phe Arg Arg Arg Gly Ser 275 280 285 Pro Glu Met Pro Phe Tyr Pro Arg Val Val Tyr Pro Ile Arg Ala Pro 290 295 300 Leu Pro Glu Asp Phe Leu Lys Ala Ser Leu Ala Tyr Gly Ile Glu Arg 305 310 315 320 Pro Thr Tyr Ile Thr Arg Ser Pro Ile Pro Ser Ser Thr Thr Pro Ser 325 330 335 Pro Ser Ala Arg Ser Ser Pro Asp Gln Ser Leu Lys Ser Ser Ser Pro 340 345 350 His Ser Ser Pro Gly Asn Thr Val Ser Pro Val Gly Pro Gly Ser Gln 355 360 365 Glu His Arg Asp Ser Tyr Ala Tyr Leu Asn Ala Ser Tyr Gly Thr Glu 370 375 380 Gly Leu Gly Ser Tyr Pro Gly Tyr Ala Pro Leu Pro His Leu Pro Pro 385 390 395 400 Ala Phe Ile Pro Ser Tyr Asn Ala His Tyr Pro Lys Phe Leu Leu Pro 405 410 415 Pro Tyr Gly Met Asn Cys Asn Gly Leu Ser Ala Val Ser Ser Met Asn 420 425 430 Gly Ile Asn Asn Phe Gly Leu Phe Pro Arg Leu Cys Pro Val Tyr Ser 435 440 445 Asn Leu Leu Gly Gly Gly Ser Leu Pro His Pro Met Leu Asn Pro Thr 450 455 460 Ser Leu Pro Ser Ser Leu Pro Ser Asp Gly Ala Arg Arg Leu Leu Gln 465 470 475 480 Pro Glu His Pro Arg Glu Val Leu Val Pro Ala Pro His Ser Ala Phe 485 490 495 Ser Phe Thr Gly Ala Ala Ala Ser Met Lys Asp Lys Ala Cys Ser Pro 500 505 510 Thr Ser Gly Ser Pro Thr Ala Gly Thr Ala Ala Thr Ala Glu His Val 515 520 525 Val Gln Pro Lys Ala Thr Ser Ala Ala Met Ala Ala Pro Ser Ser Asp 530 535 540 Glu Ala Met Asn Leu Ile Lys Asn Lys Arg Asn Met Thr Gly Tyr Lys 545 550 555 560 Thr Leu Pro Tyr Pro Leu Lys Lys Gln Asn Gly Lys Ile Lys Tyr Glu 565 570 575 Cys Asn Val Cys Ala Lys Thr Phe Gly Gln Leu Ser Asn Leu Lys Val 580 585 590 His Leu Arg Val His Ser Gly Glu Arg Pro Phe Lys Cys Gln Thr Cys 595 600 605 Asn Lys Gly Phe Thr Gln Leu Ala His Leu Gln Lys His Tyr Leu Val 610 615 620 His Thr Gly Glu Lys Pro His Glu Cys Gln Val Cys His Lys Arg Phe 625 630 635 640 Ser Ser Thr Ser Asn Leu Lys Thr His Leu Arg Leu His Ser Gly Glu 645 650 655 Lys Pro Tyr Gln Cys Lys Val Cys Pro Ala Lys Phe Thr Gln Phe Val 660 665 670 His Leu Lys Leu His Lys Arg Leu His Thr Arg Glu Arg Pro His Lys 675 680 685 Cys Ser Gln Cys His Lys Asn Tyr Ile His Leu Cys Ser Leu Lys Val 690 695 700 His Leu Lys Gly Asn Cys Ala Ala Ala Pro Ala Pro Gly Leu Pro Leu 705 710 715 720 Glu Asp Leu Thr Arg Ile Asn Glu Glu Ile Glu Lys Phe Asp Ile Ser 725 730 735 Asp Asn Ala Asp Arg Leu Glu Asp Val Glu Asp Asp Ile Ser Val Ile 740 745 750 Ser Val Val Glu Lys Glu Ile Leu Ala Val Val Arg Lys Glu Lys Glu 755 760 765 Glu Thr Gly Leu Lys Val Ser Leu Gln Arg Asn Met Gly Asn Gly Leu 770 775 780 Leu Ser Ser Gly Cys Ser Leu Tyr Glu Ser Ser Asp Leu Pro Leu Met 785 790 795 800 Lys Leu Pro Pro Ser Asn Pro Leu Pro Leu Val Pro Val Lys Val Lys 805 810 815 Gln Glu Thr Val Glu Pro Met Asp Pro 820 825 <210> 3 <211> 479 <212> PRT <213> Homo sapiens <400> 3 Met Ala Ser Thr Ile Lys Glu Ala Leu Ser Val Val Ser Glu Asp Gln 1 5 10 15 Ser Leu Phe Glu Cys Ala Tyr Gly Thr Pro His Leu Ala Lys Thr Glu 20 25 30 Met Thr Ala Ser Ser Ser Ser Asp Tyr Gly Gln Thr Ser Lys Met Ser 35 40 45 Pro Arg Val Pro Gln Gln Asp Trp Leu Ser Gln Pro Pro Ala Arg Val 50 55 60 Thr Ile Lys Met Glu Cys Asn Pro Ser Gln Val Asn Gly Ser Arg Asn 65 70 75 80 Ser Pro Asp Glu Cys Ser Val Ala Lys Gly Gly Lys Met Val Gly Ser 85 90 95 Pro Asp Thr Val Gly Met Asn Tyr Gly Ser Tyr Met Glu Glu Lys His 100 105 110 Met Pro Pro Pro Asn Met Thr Thr Asn Glu Arg Arg Val Ile Val Pro 115 120 125 Ala Asp Pro Thr Leu Trp Ser Thr Asp His Val Arg Gln Trp Leu Glu 130 135 140 Trp Ala Val Lys Glu Tyr Gly Leu Pro Asp Val Asn Ile Leu Leu Phe 145 150 155 160 Gln Asn Ile Asp Gly Lys Glu Leu Cys Lys Met Thr Lys Asp Asp Phe 165 170 175 Gln Arg Leu Thr Pro Ser Tyr Asn Ala Asp Ile Leu Leu Ser His Leu 180 185 190 His Tyr Leu Arg Glu Thr Pro Leu Pro His Leu Thr Ser Asp Asp Val 195 200 205 Asp Lys Ala Leu Gln Asn Ser Pro Arg Leu Met His Ala Arg Asn Thr 210 215 220 Gly Gly Ala Ala Phe Ile Phe Pro Asn Thr Ser Val Tyr Pro Glu Ala 225 230 235 240 Thr Gln Arg Ile Thr Thr Arg Pro Asp Leu Pro Tyr Glu Pro Pro Arg 245 250 255 Arg Ser Ala Trp Thr Gly His Gly His Pro Thr Pro Gln Ser Lys Ala 260 265 270 Ala Gln Pro Ser Pro Ser Thr Val Pro Lys Thr Glu Asp Gln Arg Pro 275 280 285 Gln Leu Asp Pro Tyr Gln Ile Leu Gly Pro Thr Ser Ser Arg Leu Ala 290 295 300 Asn Pro Gly Ser Gly Gln Ile Gln Leu Trp Gln Phe Leu Leu Glu Leu 305 310 315 320 Leu Ser Asp Ser Ser Asn Ser Ser Cys Ile Thr Trp Glu Gly Thr Asn 325 330 335 Gly Glu Phe Lys Met Thr Asp Pro Asp Glu Val Ala Arg Arg Trp Gly 340 345 350 Glu Arg Lys Ser Lys Pro Asn Met Asn Tyr Asp Lys Leu Ser Arg Ala 355 360 365 Leu Arg Tyr Tyr Tyr Asp Lys Asn Ile Met Thr Lys Val His Gly Lys 370 375 380 Arg Tyr Ala Tyr Lys Phe Asp Phe His Gly Ile Ala Gln Ala Leu Gln 385 390 395 400 Pro His Pro Pro Glu Ser Ser Leu Tyr Lys Tyr Pro Ser Asp Leu Pro 405 410 415 Tyr Met Gly Ser Tyr His Ala His Pro Gln Lys Met Asn Phe Val Ala 420 425 430 Pro His Pro Pro Ala Leu Pro Val Thr Ser Ser Ser Phe Phe Ala Ala 435 440 445 Pro Asn Pro Tyr Trp Asn Ser Pro Thr Gly Gly Ile Tyr Pro Asn Thr 450 455 460 Arg Leu Pro Thr Ser His Met Pro Ser His Leu Gly Thr Tyr Tyr 465 470 475 <210> 4 <211> 477 <212> PRT <213> Homo sapiens <400> 4 Met Asp Gly Phe Tyr Asp Gln Gln Val Pro Tyr Met Val Thr Asn Ser 1 5 10 15 Gln Arg Gly Arg Asn Cys Asn Glu Lys Pro Thr Asn Val Arg Lys Arg 20 25 30 Lys Phe Ile Asn Arg Asp Leu Ala His Asp Ser Glu Glu Leu Phe Gln 35 40 45 Asp Leu Ser Gln Leu Gln Glu Thr Trp Leu Ala Glu Ala Gln Val Pro 50 55 60 Asp Asn Asp Glu Gln Phe Val Pro Asp Tyr Gln Ala Glu Ser Leu Ala 65 70 75 80 Phe His Gly Leu Pro Leu Lys Ile Lys Lys Glu Pro His Ser Pro Cys 85 90 95 Ser Glu Ile Ser Ser Ala Cys Ser Gln Glu Gln Pro Phe Lys Phe Ser 100 105 110 Tyr Gly Glu Lys Cys Leu Tyr Asn Val Ser Ala Tyr Asp Gln Lys Pro 115 120 125 Gln Val Gly Met Arg Pro Ser Asn Pro Pro Thr Pro Ser Ser Thr Pro 130 135 140 Val Ser Pro Leu His His Ala Ser Pro Asn Ser Thr His Thr Pro Lys 145 150 155 160 Pro Asp Arg Ala Phe Pro Ala His Leu Pro Pro Ser Gln Ser Ile Pro 165 170 175 Asp Ser Ser Tyr Pro Met Asp His Arg Phe Arg Arg Gln Leu Ser Glu 180 185 190 Pro Cys Asn Ser Phe Pro Pro Leu Pro Thr Met Pro Arg Glu Gly Arg 195 200 205 Pro Met Tyr Gln Arg Gln Met Ser Glu Pro Asn Ile Pro Phe Pro Pro 210 215 220 Gln Gly Phe Lys Gln Glu Tyr His Asp Pro Val Tyr Glu His Asn Thr 225 230 235 240 Met Val Gly Ser Ala Ala Ser Gln Ser Phe Pro Pro Pro Leu Met Ile 245 250 255 Lys Gln Glu Pro Arg Asp Phe Ala Tyr Asp Ser Glu Val Pro Ser Cys 260 265 270 His Ser Ile Tyr Met Arg Gln Glu Gly Phe Leu Ala His Pro Ser Arg 275 280 285 Thr Glu Gly Cys Met Phe Glu Lys Gly Pro Arg Gln Phe Tyr Asp Asp 290 295 300 Thr Cys Val Val Pro Glu Lys Phe Asp Gly Asp Ile Lys Gln Glu Pro 305 310 315 320 Gly Met Tyr Arg Glu Gly Pro Thr Tyr Gln Arg Arg Gly Ser Leu Gln 325 330 335 Leu Trp Gln Phe Leu Val Ala Leu Leu Asp Asp Pro Ser Asn Ser His 340 345 350 Phe Ile Ala Trp Thr Gly Arg Gly Met Glu Phe Lys Leu Ile Glu Pro 355 360 365 Glu Glu Val Ala Arg Arg Trp Gly Ile Gln Lys Asn Arg Pro Ala Met 370 375 380 Asn Tyr Asp Lys Leu Ser Arg Ser Leu Arg Tyr Tyr Tyr Glu Lys Gly 385 390 395 400 Ile Met Gln Lys Val Ala Gly Glu Arg Tyr Val Tyr Lys Phe Val Cys 405 410 415 Asp Pro Glu Ala Leu Phe Ser Met Ala Phe Pro Asp Asn Gln Arg Pro 420 425 430 Leu Leu Lys Thr Asp Met Glu Arg His Ile Asn Glu Glu Asp Thr Val 435 440 445 Pro Leu Ser His Phe Asp Glu Ser Met Ala Tyr Met Pro Glu Gly Gly 450 455 460 Cys Cys Asn Pro His Pro Tyr Asn Glu Gly Tyr Val Tyr 465 470 475 <210> 5 <211> 484 <212> PRT <213> Homo sapiens <400> 5 Met Glu Arg Arg Met Lys Ala Gly Tyr Leu Asp Gln Gln Val Pro Tyr 1 5 10 15 Thr Phe Ser Ser Lys Ser Pro Gly Asn Gly Ser Leu Arg Glu Ala Leu 20 25 30 Ile Gly Pro Leu Gly Lys Leu Met Asp Pro Gly Ser Leu Pro Pro Leu 35 40 45 Asp Ser Glu Asp Leu Phe Gln Asp Leu Ser His Phe Gln Glu Thr Trp 50 55 60 Leu Ala Glu Ala Gln Val Pro Asp Ser Asp Glu Gln Phe Val Pro Asp 65 70 75 80 Phe His Ser Glu Asn Leu Ala Phe His Ser Pro Thr Thr Arg Ile Lys 85 90 95 Lys Glu Pro Gln Ser Pro Arg Thr Asp Pro Ala Leu Ser Cys Ser Arg 100 105 110 Lys Pro Pro Leu Pro Tyr His His Gly Glu Gln Cys Leu Tyr Ser Ser 115 120 125 Ala Tyr Asp Pro Pro Arg Gln Ile Ala Ile Lys Ser Pro Ala Pro Gly 130 135 140 Ala Leu Gly Gln Ser Pro Leu Gln Pro Phe Pro Arg Ala Glu Gln Arg 145 150 155 160 Asn Phe Leu Arg Ser Ser Gly Thr Ser Gln Pro His Pro Gly His Gly 165 170 175 Tyr Leu Gly Glu His Ser Ser Val Phe Gln Gln Pro Leu Asp Ile Cys 180 185 190 His Ser Phe Thr Ser Gln Gly Gly Gly Arg Glu Pro Leu Pro Ala Pro 195 200 205 Tyr Gln His Gln Leu Ser Glu Pro Cys Pro Pro Tyr Pro Gln Gln Ser 210 215 220 Phe Lys Gln Glu Tyr His Asp Pro Leu Tyr Glu Gln Ala Gly Gln Pro 225 230 235 240 Ala Val Asp Gln Gly Gly Val Asn Gly His Arg Tyr Pro Gly Ala Gly 245 250 255 Val Val Ile Lys Gln Glu Gln Thr Asp Phe Ala Tyr Asp Ser Asp Val 260 265 270 Thr Gly Cys Ala Ser Met Tyr Leu His Thr Glu Gly Phe Ser Gly Pro 275 280 285 Ser Pro Gly Asp Gly Ala Met Gly Tyr Gly Tyr Glu Lys Pro Leu Arg 290 295 300 Pro Phe Pro Asp Asp Val Cys Val Val Pro Glu Lys Phe Glu Gly Asp 305 310 315 320 Ile Lys Gln Glu Gly Val Gly Ala Phe Arg Glu Gly Pro Pro Tyr Gln 325 330 335 Arg Arg Gly Ala Leu Gln Leu Trp Gln Phe Leu Val Ala Leu Leu Asp 340 345 350 Asp Pro Thr Asn Ala His Phe Ile Ala Trp Thr Gly Arg Gly Met Glu 355 360 365 Phe Lys Leu Ile Glu Pro Glu Glu Val Ala Arg Leu Trp Gly Ile Gln 370 375 380 Lys Asn Arg Pro Ala Met Asn Tyr Asp Lys Leu Ser Arg Ser Leu Arg 385 390 395 400 Tyr Tyr Tyr Glu Lys Gly Ile Met Gln Lys Val Ala Gly Glu Arg Tyr 405 410 415 Val Tyr Lys Phe Val Cys Glu Pro Glu Ala Leu Phe Ser Leu Ala Phe 420 425 430 Pro Asp Asn Gln Arg Pro Ala Leu Lys Ala Glu Phe Asp Arg Pro Val 435 440 445 Ser Glu Glu Asp Thr Val Pro Leu Ser His Leu Asp Glu Ser Pro Ala 450 455 460 Tyr Leu Pro Glu Leu Ala Gly Pro Ala Gln Pro Phe Gly Pro Lys Gly 465 470 475 480 Gly Tyr Ser Tyr <210> 6 <211> 510 <212> PRT <213> Homo sapiens <400> 6 Met Asp Gly Phe Tyr Asp Gln Gln Val Pro Phe Met Val Pro Gly Lys 1 5 10 15 Ser Arg Ser Glu Glu Cys Arg Gly Arg Pro Val Ile Asp Arg Lys Arg 20 25 30 Lys Phe Leu Asp Thr Asp Leu Ala His Asp Ser Glu Glu Leu Phe Gln 35 40 45 Asp Leu Ser Gln Leu Gln Glu Ala Trp Leu Ala Glu Ala Gln Val Pro 50 55 60 Asp Asp Glu Gln Phe Val Pro Asp Phe Gln Ser Asp Asn Leu Val Leu 65 70 75 80 His Ala Pro Pro Pro Thr Lys Ile Lys Arg Glu Leu His Ser Pro Ser 85 90 95 Ser Glu Leu Ser Ser Cys Ser His Glu Gln Ala Leu Gly Ala Asn Tyr 100 105 110 Gly Glu Lys Cys Leu Tyr Asn Tyr Cys Ala Tyr Asp Arg Lys Pro Pro 115 120 125 Ser Gly Phe Lys Pro Leu Thr Pro Pro Thr Thr Pro Leu Ser Pro Thr 130 135 140 His Gln Asn Pro Leu Phe Pro Pro Pro Gln Ala Thr Leu Pro Thr Ser 145 150 155 160 Gly His Ala Pro Ala Ala Gly Pro Val Gln Gly Val Gly Pro Ala Pro 165 170 175 Ala Pro His Ser Leu Pro Glu Pro Gly Pro Gln Gln Gln Thr Phe Ala 180 185 190 Val Pro Arg Pro Pro His Gln Pro Leu Gln Met Pro Lys Met Met Pro 195 200 205 Glu Asn Gln Tyr Pro Ser Glu Gln Arg Phe Gln Arg Gln Leu Ser Glu 210 215 220 Pro Cys His Pro Phe Pro Pro Gln Pro Gly Val Pro Gly Asp Asn Arg 225 230 235 240 Pro Ser Tyr His Arg Gln Met Ser Glu Pro Ile Val Pro Ala Ala Pro 245 250 255 Pro Pro Pro Gln Gly Phe Lys Gln Glu Tyr His Asp Pro Leu Tyr Glu 260 265 270 His Gly Val Pro Gly Met Pro Gly Pro Pro Ala His Gly Phe Gln Ser 275 280 285 Pro Met Gly Ile Lys Gln Glu Pro Arg Asp Tyr Cys Val Asp Ser Glu 290 295 300 Val Pro Asn Cys Gln Ser Ser Tyr Met Arg Gly Gly Tyr Phe Ser Ser 305 310 315 320 Ser His Glu Gly Phe Ser Tyr Glu Lys Asp Pro Arg Leu Tyr Phe Asp 325 330 335 Asp Thr Cys Val Val Pro Glu Arg Leu Glu Gly Lys Val Lys Gln Glu 340 345 350 Pro Thr Met Tyr Arg Glu Gly Pro Pro Tyr Gln Arg Arg Gly Ser Leu 355 360 365 Gln Leu Trp Gln Phe Leu Val Thr Leu Leu Asp Asp Pro Ala Asn Ala 370 375 380 His Phe Ile Ala Trp Thr Gly Arg Gly Met Glu Phe Lys Leu Ile Glu 385 390 395 400 Pro Glu Glu Val Ala Arg Arg Trp Gly Ile Gln Lys Asn Arg Pro Ala 405 410 415 Met Asn Tyr Asp Lys Leu Ser Arg Ser Leu Arg Tyr Tyr Tyr Glu Lys 420 425 430 Gly Ile Met Gln Lys Val Ala Gly Glu Arg Tyr Val Tyr Lys Phe Val 435 440 445 Cys Asp Pro Asp Ala Leu Phe Ser Met Ala Phe Pro Asp Asn Gln Arg 450 455 460 Pro Phe Leu Lys Ala Glu Ser Glu Cys His Leu Ser Glu Glu Asp Thr 465 470 475 480 Leu Pro Leu Thr His Phe Glu Asp Ser Pro Ala Tyr Leu Leu Asp Met 485 490 495 Asp Arg Cys Ser Ser Leu Pro Tyr Ala Glu Gly Phe Ala Tyr 500 505 510 <210> 7 <211> 452 <212> PRT <213> Homo sapiens <400> 7 Met Ser Glu Thr Pro Ala Gln Cys Ser Ile Lys Gln Glu Arg Ile Ser 1 5 10 15 Tyr Thr Pro Pro Glu Ser Pro Val Pro Ser Tyr Ala Ser Ser Thr Pro 20 25 30 Leu His Val Pro Val Pro Arg Ala Leu Arg Met Glu Glu Asp Ser Ile 35 40 45 Arg Leu Pro Ala His Leu Arg Leu Gln Pro Ile Tyr Trp Ser Arg Asp 50 55 60 Asp Val Ala Gln Trp Leu Lys Trp Ala Glu Asn Glu Phe Ser Leu Arg 65 70 75 80 Pro Ile Asp Ser Asn Thr Phe Glu Met Asn Gly Lys Ala Leu Leu Leu 85 90 95 Leu Thr Lys Glu Asp Phe Arg Tyr Arg Ser Pro His Ser Gly Asp Val 100 105 110 Leu Tyr Glu Leu Leu Gln His Ile Leu Lys Gln Arg Lys Pro Arg Ile 115 120 125 Leu Phe Ser Pro Phe Phe His Pro Gly Asn Ser Ile His Thr Gln Pro 130 135 140 Glu Val Ile Leu His Gln Asn His Glu Glu Asp Asn Cys Val Gln Arg 145 150 155 160 Thr Pro Arg Pro Ser Val Asp Asn Val His His Asn Pro Pro Thr Ile 165 170 175 Glu Leu Leu His Arg Ser Arg Ser Pro Ile Thr Thr Asn His Arg Pro 180 185 190 Ser Pro Asp Pro Glu Gln Arg Pro Leu Arg Ser Pro Leu Asp Asn Met 195 200 205 Ile Arg Arg Leu Ser Pro Ala Glu Arg Ala Gln Gly Pro Arg Pro His 210 215 220 Gln Glu Asn Asn His Gln Glu Ser Tyr Pro Leu Ser Val Ser Pro Met 225 230 235 240 Glu Asn Asn His Cys Pro Ala Ser Ser Glu Ser His Pro Lys Pro Ser 245 250 255 Ser Pro Arg Gln Glu Ser Thr Arg Val Ile Gln Leu Met Pro Ser Pro 260 265 270 Ile Met His Pro Leu Ile Leu Asn Pro Arg His Ser Val Asp Phe Lys 275 280 285 Gln Ser Arg Leu Ser Glu Asp Gly Leu His Arg Glu Gly Lys Pro Ile 290 295 300 Asn Leu Ser His Arg Glu Asp Leu Ala Tyr Met Asn His Ile Met Val 305 310 315 320 Ser Val Ser Pro Pro Glu Glu His Ala Met Pro Ile Gly Arg Ile Ala 325 330 335 Asp Cys Arg Leu Leu Trp Asp Tyr Val Tyr Gln Leu Leu Ser Asp Ser 340 345 350 Arg Tyr Glu Asn Phe Ile Arg Trp Glu Asp Lys Glu Ser Lys Ile Phe 355 360 365 Arg Ile Val Asp Pro Asn Gly Leu Ala Arg Leu Trp Gly Asn His Lys 370 375 380 Asn Arg Thr Asn Met Thr Tyr Glu Lys Met Ser Arg Ala Leu Arg His 385 390 395 400 Tyr Tyr Lys Leu Asn Ile Ile Arg Lys Glu Pro Gly Gln Arg Leu Leu 405 410 415 Phe Arg Phe Met Lys Thr Pro Asp Glu Ile Met Ser Gly Arg Thr Asp 420 425 430 Arg Leu Glu His Leu Glu Ser Gln Glu Leu Asp Glu Gln Ile Tyr Gln 435 440 445 Glu Asp Glu Cys 450 <210> 8 <211> 403 <212> PRT <213> Homo sapiens <400> 8 Met Thr Ala Ile Ile Lys Glu Ile Val Ser Arg Asn Lys Arg Arg Tyr 1 5 10 15 Gln Glu Asp Gly Phe Asp Leu Asp Leu Thr Tyr Ile Tyr Pro Asn Ile 20 25 30 Ile Ala Met Gly Phe Pro Ala Glu Arg Leu Glu Gly Val Tyr Arg Asn 35 40 45 Asn Ile Asp Asp Val Val Arg Phe Leu Asp Ser Lys His Lys Asn His 50 55 60 Tyr Lys Ile Tyr Asn Leu Cys Ala Glu Arg His Tyr Asp Thr Ala Lys 65 70 75 80 Phe Asn Cys Arg Val Ala Gln Tyr Pro Phe Glu Asp His Asn Pro Pro 85 90 95 Gln Leu Glu Leu Ile Lys Pro Phe Cys Glu Asp Leu Asp Gln Trp Leu 100 105 110 Ser Glu Asp Asp Asn His Val Ala Ala Ile His Cys Lys Ala Gly Lys 115 120 125 Gly Arg Thr Gly Val Met Ile Cys Ala Tyr Leu Leu His Arg Gly Lys 130 135 140 Phe Leu Lys Ala Gln Glu Ala Leu Asp Phe Tyr Gly Glu Val Arg Thr 145 150 155 160 Arg Asp Lys Lys Gly Val Thr Ile Pro Ser Gln Arg Arg Tyr Val Tyr 165 170 175 Tyr Tyr Ser Tyr Leu Leu Lys Asn His Leu Asp Tyr Arg Pro Val Ala 180 185 190 Leu Leu Phe His Lys Met Met Phe Glu Thr Ile Pro Met Phe Ser Gly 195 200 205 Gly Thr Cys Asn Pro Gln Phe Val Val Cys Gln Leu Lys Val Lys Ile 210 215 220 Tyr Ser Ser Asn Ser Gly Pro Thr Arg Arg Glu Asp Lys Phe Met Tyr 225 230 235 240 Phe Glu Phe Pro Gln Pro Leu Pro Val Cys Gly Asp Ile Lys Val Glu 245 250 255 Phe Phe His Lys Gln Asn Lys Met Leu Lys Lys Asp Lys Met Phe His 260 265 270 Phe Trp Val Asn Thr Phe Phe Ile Pro Gly Pro Glu Glu Thr Ser Glu 275 280 285 Lys Val Glu Asn Gly Ser Leu Cys Asp Gln Glu Ile Asp Ser Ile Cys 290 295 300 Ser Ile Glu Arg Ala Asp Asn Asp Lys Glu Tyr Leu Val Leu Thr Leu 305 310 315 320 Thr Lys Asn Asp Leu Asp Lys Ala Asn Lys Asp Lys Ala Asn Arg Tyr 325 330 335 Phe Ser Pro Asn Phe Lys Val Lys Leu Tyr Phe Thr Lys Thr Val Glu 340 345 350 Glu Pro Ser Asn Pro Glu Ala Ser Ser Ser Thr Ser Val Thr Pro Asp 355 360 365 Val Ser Asp Asn Glu Pro Asp His Tyr Arg Tyr Ser Asp Thr Thr Asp 370 375 380 Ser Asp Pro Glu Asn Glu Pro Phe Asp Glu Asp Gln His Thr Gln Ile 385 390 395 400 Thr Lys Val <210> 9 <211> 393 <212> PRT <213> Homo sapiens <400> 9 Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln 1 5 10 15 Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu 20 25 30 Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp 35 40 45 Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro 50 55 60 Arg Met Pro Glu Ala Ala Pro Pro Val Ala Pro Ala Pro Ala Ala Pro 65 70 75 80 Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser 85 90 95 Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly 100 105 110 Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro 115 120 125 Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln 130 135 140 Leu Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met 145 150 155 160 Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys 165 170 175 Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln 180 185 190 His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp 195 200 205 Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu 210 215 220 Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser 225 230 235 240 Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr 245 250 255 Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val 260 265 270 Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn 275 280 285 Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr 290 295 300 Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys 305 310 315 320 Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu 325 330 335 Arg Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp 340 345 350 Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His 355 360 365 Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met 370 375 380 Phe Lys Thr Glu Gly Pro Asp Ser Asp 385 390 <210> 10 <211> 1068 <212> PRT <213> Homo sapiens <400> 10 Met Pro Pro Arg Pro Ser Ser Gly Glu Leu Trp Gly Ile His Leu Met 1 5 10 15 Pro Pro Arg Ile Leu Val Glu Cys Leu Leu Pro Asn Gly Met Ile Val 20 25 30 Thr Leu Glu Cys Leu Arg Glu Ala Thr Leu Ile Thr Ile Lys His Glu 35 40 45 Leu Phe Lys Glu Ala Arg Lys Tyr Pro Leu His Gln Leu Leu Gln Asp 50 55 60 Glu Ser Ser Tyr Ile Phe Val Ser Val Thr Gln Glu Ala Glu Arg Glu 65 70 75 80 Glu Phe Phe Asp Glu Thr Arg Arg Leu Cys Asp Leu Arg Leu Phe Gln 85 90 95 Pro Phe Leu Lys Val Ile Glu Pro Val Gly Asn Arg Glu Glu Lys Ile 100 105 110 Leu Asn Arg Glu Ile Gly Phe Ala Ile Gly Met Pro Val Cys Glu Phe 115 120 125 Asp Met Val Lys Asp Pro Glu Val Gln Asp Phe Arg Arg Asn Ile Leu 130 135 140 Asn Val Cys Lys Glu Ala Val Asp Leu Arg Asp Leu Asn Ser Pro His 145 150 155 160 Ser Arg Ala Met Tyr Val Tyr Pro Pro Asn Val Glu Ser Ser Pro Glu 165 170 175 Leu Pro Lys His Ile Tyr Asn Lys Leu Asp Lys Gly Gln Ile Ile Val 180 185 190 Val Ile Trp Val Ile Val Ser Pro Asn Asn Asp Lys Gln Lys Tyr Thr 195 200 205 Leu Lys Ile Asn His Asp Cys Val Pro Glu Gln Val Ile Ala Glu Ala 210 215 220 Ile Arg Lys Lys Thr Arg Ser Met Leu Leu Ser Ser Glu Gln Leu Lys 225 230 235 240 Leu Cys Val Leu Glu Tyr Gln Gly Lys Tyr Ile Leu Lys Val Cys Gly 245 250 255 Cys Asp Glu Tyr Phe Leu Glu Lys Tyr Pro Leu Ser Gln Tyr Lys Tyr 260 265 270 Ile Arg Ser Cys Ile Met Leu Gly Arg Met Pro Asn Leu Met Leu Met 275 280 285 Ala Lys Glu Ser Leu Tyr Ser Gln Leu Pro Met Asp Cys Phe Thr Met 290 295 300 Pro Ser Tyr Ser Arg Arg Ile Ser Thr Ala Thr Pro Tyr Met Asn Gly 305 310 315 320 Glu Thr Ser Thr Lys Ser Leu Trp Val Ile Asn Ser Ala Leu Arg Ile 325 330 335 Lys Ile Leu Cys Ala Thr Tyr Val Asn Val Asn Ile Arg Asp Ile Asp 340 345 350 Lys Ile Tyr Val Arg Thr Gly Ile Tyr His Gly Gly Glu Pro Leu Cys 355 360 365 Asp Asn Val Asn Thr Gln Arg Val Pro Cys Ser Asn Pro Arg Trp Asn 370 375 380 Glu Trp Leu Asn Tyr Asp Ile Tyr Ile Pro Asp Leu Pro Arg Ala Ala 385 390 395 400 Arg Leu Cys Leu Ser Ile Cys Ser Val Lys Gly Arg Lys Gly Ala Lys 405 410 415 Glu Glu His Cys Pro Leu Ala Trp Gly Asn Ile Asn Leu Phe Asp Tyr 420 425 430 Thr Asp Thr Leu Val Ser Gly Lys Met Ala Leu Asn Leu Trp Pro Val 435 440 445 Pro His Gly Leu Glu Asp Leu Leu Asn Pro Ile Gly Val Thr Gly Ser 450 455 460 Asn Pro Asn Lys Glu Thr Pro Cys Leu Glu Leu Glu Phe Asp Trp Phe 465 470 475 480 Ser Ser Val Val Lys Phe Pro Asp Met Ser Val Ile Glu Glu His Ala 485 490 495 Asn Trp Ser Val Ser Arg Glu Ala Gly Phe Ser Tyr Ser His Ala Gly 500 505 510 Leu Ser Asn Arg Leu Ala Arg Asp Asn Glu Leu Arg Glu Asn Asp Lys 515 520 525 Glu Gln Leu Lys Ala Ile Ser Thr Arg Asp Pro Leu Ser Glu Ile Thr 530 535 540 Glu Gln Glu Lys Asp Phe Leu Trp Ser His Arg His Tyr Cys Val Thr 545 550 555 560 Ile Pro Glu Ile Leu Pro Lys Leu Leu Leu Ser Val Lys Trp Asn Ser 565 570 575 Arg Asp Glu Val Ala Gln Met Tyr Cys Leu Val Lys Asp Trp Pro Pro 580 585 590 Ile Lys Pro Glu Gln Ala Met Glu Leu Leu Asp Cys Asn Tyr Pro Asp 595 600 605 Pro Met Val Arg Gly Phe Ala Val Arg Cys Leu Glu Lys Tyr Leu Thr 610 615 620 Asp Asp Lys Leu Ser Gln Tyr Leu Ile Gln Leu Val Gln Val Leu Lys 625 630 635 640 Tyr Glu Gln Tyr Leu Asp Asn Leu Leu Val Arg Phe Leu Leu Lys Lys 645 650 655 Ala Leu Thr Asn Gln Arg Ile Gly His Phe Phe Phe Trp His Leu Lys 660 665 670 Ser Glu Met His Asn Lys Thr Val Ser Gln Arg Phe Gly Leu Leu Leu 675 680 685 Glu Ser Tyr Cys Arg Ala Cys Gly Met Tyr Leu Lys His Leu Asn Arg 690 695 700 Gln Val Glu Ala Met Glu Lys Leu Ile Asn Leu Thr Asp Ile Leu Lys 705 710 715 720 Gln Glu Lys Lys Asp Glu Thr Gln Lys Val Gln Met Lys Phe Leu Val 725 730 735 Glu Gln Met Arg Arg Pro Asp Phe Met Asp Ala Leu Gln Gly Phe Leu 740 745 750 Ser Pro Leu Asn Pro Ala His Gln Leu Gly Asn Leu Arg Leu Glu Glu 755 760 765 Cys Arg Ile Met Ser Ser Ala Lys Arg Pro Leu Trp Leu Asn Trp Glu 770 775 780 Asn Pro Asp Ile Met Ser Glu Leu Leu Phe Gln Asn Asn Glu Ile Ile 785 790 795 800 Phe Lys Asn Gly Asp Asp Leu Arg Gln Asp Met Leu Thr Leu Gln Ile 805 810 815 Ile Arg Ile Met Glu Asn Ile Trp Gln Asn Gln Gly Leu Asp Leu Arg 820 825 830 Met Leu Pro Tyr Gly Cys Leu Ser Ile Gly Asp Cys Val Gly Leu Ile 835 840 845 Glu Val Val Arg Asn Ser His Thr Ile Met Gln Ile Gln Cys Lys Gly 850 855 860 Gly Leu Lys Gly Ala Leu Gln Phe Asn Ser His Thr Leu His Gln Trp 865 870 875 880 Leu Lys Asp Lys Asn Lys Gly Glu Ile Tyr Asp Ala Ala Ile Asp Leu 885 890 895 Phe Thr Arg Ser Cys Ala Gly Tyr Cys Val Ala Thr Phe Ile Leu Gly 900 905 910 Ile Gly Asp Arg His Asn Ser Asn Ile Met Val Lys Asp Asp Gly Gln 915 920 925 Leu Phe His Ile Asp Phe Gly His Phe Leu Asp His Lys Lys Lys Lys 930 935 940 Phe Gly Tyr Lys Arg Glu Arg Val Pro Phe Val Leu Thr Gln Asp Phe 945 950 955 960 Leu Ile Val Ile Ser Lys Gly Ala Gln Glu Cys Thr Lys Thr Arg Glu 965 970 975 Phe Glu Arg Phe Gln Glu Met Cys Tyr Lys Ala Tyr Leu Ala Ile Arg 980 985 990 Gln His Ala Asn Leu Phe Ile Asn Leu Phe Ser Met Met Leu Gly Ser 995 1000 1005 Gly Met Pro Glu Leu Gln Ser Phe Asp Asp Ile Ala Tyr Ile Arg Lys 1010 1015 1020 Thr Leu Ala Leu Asp Lys Thr Glu Gln Glu Ala Leu Glu Tyr Phe Met 1025 1030 1035 1040 Lys Gln Met Asn Asp Ala His His Gly Gly Trp Thr Thr Lys Met Asp 1045 1050 1055 Trp Ile Phe His Thr Ile Lys Gln His Ala Leu Asn 1060 1065 <210> 11 <211> 1052 <212> PRT <213> Homo sapiens <400> 11 Met Ala Ala Ala Tyr Leu Asp Pro Asn Leu Asn His Thr Pro Asn Ser 1 5 10 15 Ser Thr Lys Thr His Leu Gly Thr Gly Met Glu Arg Ser Pro Gly Ala 20 25 30 Met Glu Arg Val Leu Lys Val Phe His Tyr Phe Glu Ser Asn Ser Glu 35 40 45 Pro Thr Thr Trp Ala Ser Ile Ile Arg His Gly Asp Ala Thr Asp Val 50 55 60 Arg Gly Ile Ile Gln Lys Ile Val Asp Ser His Lys Val Lys His Val 65 70 75 80 Ala Cys Tyr Gly Phe Arg Leu Ser His Leu Arg Ser Glu Glu Val His 85 90 95 Trp Leu His Val Asp Met Gly Val Ser Ser Val Arg Glu Lys Tyr Glu 100 105 110 Leu Ala His Pro Pro Glu Glu Trp Lys Tyr Glu Leu Arg Ile Arg Tyr 115 120 125 Leu Pro Lys Gly Phe Leu Asn Gln Phe Thr Glu Asp Lys Pro Thr Leu 130 135 140 Asn Phe Phe Tyr Gln Gln Val Lys Ser Asp Tyr Met Leu Glu Ile Ala 145 150 155 160 Asp Gln Val Asp Gln Glu Ile Ala Leu Lys Leu Gly Cys Leu Glu Ile 165 170 175 Arg Arg Ser Tyr Trp Glu Met Arg Gly Asn Ala Leu Glu Lys Lys Ser 180 185 190 Asn Tyr Glu Val Leu Glu Lys Asp Val Gly Leu Lys Arg Phe Phe Pro 195 200 205 Lys Ser Leu Leu Asp Ser Val Lys Ala Lys Thr Leu Arg Lys Leu Ile 210 215 220 Gln Gln Thr Phe Arg Gln Phe Ala Asn Leu Asn Arg Glu Glu Ser Ile 225 230 235 240 Leu Lys Phe Phe Glu Ile Leu Ser Pro Val Tyr Arg Phe Asp Lys Glu 245 250 255 Cys Phe Lys Cys Ala Leu Gly Ser Ser Trp Ile Ile Ser Val Glu Leu 260 265 270 Ala Ile Gly Pro Glu Glu Gly Ile Ser Tyr Leu Thr Asp Lys Gly Cys 275 280 285 Asn Pro Thr His Leu Ala Asp Phe Thr Gln Val Gln Thr Ile Gln Tyr 290 295 300 Ser Asn Ser Glu Asp Lys Asp Arg Lys Gly Met Leu Gln Leu Lys Ile 305 310 315 320 Ala Gly Ala Pro Glu Pro Leu Thr Val Thr Ala Pro Ser Leu Thr Ile 325 330 335 Ala Glu Asn Met Ala Asp Leu Ile Asp Gly Tyr Cys Arg Leu Val Asn 340 345 350 Gly Thr Ser Gln Ser Phe Ile Ile Arg Pro Gln Lys Glu Gly Glu Arg 355 360 365 Ala Leu Pro Ser Ile Pro Lys Leu Ala Asn Ser Glu Lys Gln Gly Met 370 375 380 Arg Thr His Ala Val Ser Val Ser Glu Thr Asp Asp Tyr Ala Glu Ile 385 390 395 400 Ile Asp Glu Glu Asp Thr Tyr Thr Met Pro Ser Thr Arg Asp Tyr Glu 405 410 415 Ile Gln Arg Glu Arg Ile Glu Leu Gly Arg Cys Ile Gly Glu Gly Gln 420 425 430 Phe Gly Asp Val His Gln Gly Ile Tyr Met Ser Pro Glu Asn Pro Ala 435 440 445 Leu Ala Val Ala Ile Lys Thr Cys Lys Asn Cys Thr Ser Asp Ser Val 450 455 460 Arg Glu Lys Phe Leu Gln Glu Ala Leu Thr Met Arg Gln Phe Asp His 465 470 475 480 Pro His Ile Val Lys Leu Ile Gly Val Ile Thr Glu Asn Pro Val Trp 485 490 495 Ile Ile Met Glu Leu Cys Thr Leu Gly Glu Leu Arg Ser Phe Leu Gln 500 505 510 Val Arg Lys Tyr Ser Leu Asp Leu Ala Ser Leu Ile Leu Tyr Ala Tyr 515 520 525 Gln Leu Ser Thr Ala Leu Ala Tyr Leu Glu Ser Lys Arg Phe Val His 530 535 540 Arg Asp Ile Ala Ala Arg Asn Val Leu Val Ser Ser Asn Asp Cys Val 545 550 555 560 Lys Leu Gly Asp Phe Gly Leu Ser Arg Tyr Met Glu Asp Ser Thr Tyr 565 570 575 Tyr Lys Ala Ser Lys Gly Lys Leu Pro Ile Lys Trp Met Ala Pro Glu 580 585 590 Ser Ile Asn Phe Arg Arg Phe Thr Ser Ala Ser Asp Val Trp Met Phe 595 600 605 Gly Val Cys Met Trp Glu Ile Leu Met His Gly Val Lys Pro Phe Gln 610 615 620 Gly Val Lys Asn Asn Asp Val Ile Gly Arg Ile Glu Asn Gly Glu Arg 625 630 635 640 Leu Pro Met Pro Pro Asn Cys Pro Pro Thr Leu Tyr Ser Leu Met Thr 645 650 655 Lys Cys Trp Ala Tyr Asp Pro Ser Arg Arg Pro Arg Phe Thr Glu Leu 660 665 670 Lys Ala Gln Leu Ser Thr Ile Leu Glu Glu Glu Lys Ala Gln Gln Glu 675 680 685 Glu Arg Met Arg Met Glu Ser Arg Arg Gln Ala Thr Val Ser Trp Asp 690 695 700 Ser Gly Gly Ser Asp Glu Ala Pro Pro Lys Pro Ser Arg Pro Gly Tyr 705 710 715 720 Pro Ser Pro Arg Ser Ser Glu Gly Phe Tyr Pro Ser Pro Gln His Met 725 730 735 Val Gln Thr Asn His Tyr Gln Val Ser Gly Tyr Pro Gly Ser His Gly 740 745 750 Ile Thr Ala Met Ala Gly Ser Ile Tyr Pro Gly Gln Ala Ser Leu Leu 755 760 765 Asp Gln Thr Asp Ser Trp Asn His Arg Pro Gln Glu Ile Ala Met Trp 770 775 780 Gln Pro Asn Val Glu Asp Ser Thr Val Leu Asp Leu Arg Gly Ile Gly 785 790 795 800 Gln Val Leu Pro Thr His Leu Met Glu Glu Arg Leu Ile Arg Gln Gln 805 810 815 Gln Glu Met Glu Glu Asp Gln Arg Trp Leu Glu Lys Glu Glu Arg Phe 820 825 830 Leu Lys Pro Asp Val Arg Leu Ser Arg Gly Ser Ile Asp Arg Glu Asp 835 840 845 Gly Ser Leu Gln Gly Pro Ile Gly Asn Gln His Ile Tyr Gln Pro Val 850 855 860 Gly Lys Pro Asp Pro Ala Ala Pro Pro Lys Lys Pro Pro Arg Pro Gly 865 870 875 880 Ala Pro Gly His Leu Gly Ser Leu Ala Ser Leu Ser Ser Pro Ala Asp 885 890 895 Ser Tyr Asn Glu Gly Val Lys Leu Gln Pro Gln Glu Ile Ser Pro Pro 900 905 910 Pro Thr Ala Asn Leu Asp Arg Ser Asn Asp Lys Val Tyr Glu Asn Val 915 920 925 Thr Gly Leu Val Lys Ala Val Ile Glu Met Ser Ser Lys Ile Gln Pro 930 935 940 Ala Pro Pro Glu Glu Tyr Val Pro Met Val Lys Glu Val Gly Leu Ala 945 950 955 960 Leu Arg Thr Leu Leu Ala Thr Val Asp Glu Thr Ile Pro Leu Leu Pro 965 970 975 Ala Ser Thr His Arg Glu Ile Glu Met Ala Gln Lys Leu Leu Asn Ser 980 985 990 Asp Leu Gly Glu Leu Ile Asn Lys Met Lys Leu Ala Gln Gln Tyr Val 995 1000 1005 Met Thr Ser Leu Gln Gln Glu Tyr Lys Lys Gln Met Leu Thr Ala Ala 1010 1015 1020 His Ala Leu Ala Val Asp Ala Lys Asn Leu Leu Asp Val Ile Asp Gln 1025 1030 1035 1040 Ala Arg Leu Lys Met Leu Gly Gln Thr Arg Pro His 1045 1050 <210> 12 <211> 928 <212> PRT <213> Homo sapiens <400> 12 Met Pro Pro Lys Thr Pro Arg Lys Thr Ala Ala Thr Ala Ala Ala Ala 1 5 10 15 Ala Ala Glu Pro Pro Ala Pro Pro Pro Pro Pro Pro Pro Glu Glu Asp 20 25 30 Pro Glu Gln Asp Ser Gly Pro Glu Asp Leu Pro Leu Val Arg Leu Glu 35 40 45 Phe Glu Glu Thr Glu Glu Pro Asp Phe Thr Ala Leu Cys Gln Lys Leu 50 55 60 Lys Ile Pro Asp His Val Arg Glu Arg Ala Trp Leu Thr Trp Glu Lys 65 70 75 80 Val Ser Ser Val Asp Gly Val Leu Gly Gly Tyr Ile Gln Lys Lys Lys 85 90 95 Glu Leu Trp Gly Ile Cys Ile Phe Ile Ala Ala Val Asp Leu Asp Glu 100 105 110 Met Ser Phe Thr Phe Thr Glu Leu Gln Lys Asn Ile Glu Ile Ser Val 115 120 125 His Lys Phe Phe Asn Leu Leu Lys Glu Ile Asp Thr Ser Thr Lys Val 130 135 140 Asp Asn Ala Met Ser Arg Leu Leu Lys Lys Tyr Asp Val Leu Phe Ala 145 150 155 160 Leu Phe Ser Lys Leu Glu Arg Thr Cys Glu Leu Ile Tyr Leu Thr Gln 165 170 175 Pro Ser Ser Ser Ile Ser Thr Glu Ile Asn Ser Ala Leu Val Leu Lys 180 185 190 Val Ser Trp Ile Thr Phe Leu Leu Ala Lys Gly Glu Val Leu Gln Met 195 200 205 Glu Asp Asp Leu Val Ile Ser Phe Gln Leu Met Leu Cys Val Leu Asp 210 215 220 Tyr Phe Ile Lys Leu Ser Pro Pro Met Leu Leu Lys Glu Pro Tyr Lys 225 230 235 240 Thr Ala Val Ile Pro Ile Asn Gly Ser Pro Arg Thr Pro Arg Arg Gly 245 250 255 Gln Asn Arg Ser Ala Arg Ile Ala Lys Gln Leu Glu Asn Asp Thr Arg 260 265 270 Ile Ile Glu Val Leu Cys Lys Glu His Glu Cys Asn Ile Asp Glu Val 275 280 285 Lys Asn Val Tyr Phe Lys Asn Phe Ile Pro Phe Met Asn Ser Leu Gly 290 295 300 Leu Val Thr Ser Asn Gly Leu Pro Glu Val Glu Asn Leu Ser Lys Arg 305 310 315 320 Tyr Glu Glu Ile Tyr Leu Lys Asn Lys Asp Leu Asp Ala Arg Leu Phe 325 330 335 Leu Asp His Asp Lys Thr Leu Gln Thr Asp Ser Ile Asp Ser Phe Glu 340 345 350 Thr Gln Arg Thr Pro Arg Lys Ser Asn Leu Asp Glu Glu Val Asn Val 355 360 365 Ile Pro Pro His Thr Pro Val Arg Thr Val Met Asn Thr Ile Gln Gln 370 375 380 Leu Met Met Ile Leu Asn Ser Ala Ser Asp Gln Pro Ser Glu Asn Leu 385 390 395 400 Ile Ser Tyr Phe Asn Asn Cys Thr Val Asn Pro Lys Glu Ser Ile Leu 405 410 415 Lys Arg Val Lys Asp Ile Gly Tyr Ile Phe Lys Glu Lys Phe Ala Lys 420 425 430 Ala Val Gly Gln Gly Cys Val Glu Ile Gly Ser Gln Arg Tyr Lys Leu 435 440 445 Gly Val Arg Leu Tyr Tyr Arg Val Met Glu Ser Met Leu Lys Ser Glu 450 455 460 Glu Glu Arg Leu Ser Ile Gln Asn Phe Ser Lys Leu Leu Asn Asp Asn 465 470 475 480 Ile Phe His Met Ser Leu Leu Ala Cys Ala Leu Glu Val Val Met Ala 485 490 495 Thr Tyr Ser Arg Ser Thr Ser Gln Asn Leu Asp Ser Gly Thr Asp Leu 500 505 510 Ser Phe Pro Trp Ile Leu Asn Val Leu Asn Leu Lys Ala Phe Asp Phe 515 520 525 Tyr Lys Val Ile Glu Ser Phe Ile Lys Ala Glu Gly Asn Leu Thr Arg 530 535 540 Glu Met Ile Lys His Leu Glu Arg Cys Glu His Arg Ile Met Glu Ser 545 550 555 560 Leu Ala Trp Leu Ser Asp Ser Pro Leu Phe Asp Leu Ile Lys Gln Ser 565 570 575 Lys Asp Arg Glu Gly Pro Thr Asp His Leu Glu Ser Ala Cys Pro Leu 580 585 590 Asn Leu Pro Leu Gln Asn Asn His Thr Ala Ala Asp Met Tyr Leu Ser 595 600 605 Pro Val Arg Ser Pro Lys Lys Lys Gly Ser Thr Thr Arg Val Asn Ser 610 615 620 Thr Ala Asn Ala Glu Thr Gln Ala Thr Ser Ala Phe Gln Thr Gln Lys 625 630 635 640 Pro Leu Lys Ser Thr Ser Leu Ser Leu Phe Tyr Lys Lys Val Tyr Arg 645 650 655 Leu Ala Tyr Leu Arg Leu Asn Thr Leu Cys Glu Arg Leu Leu Ser Glu 660 665 670 His Pro Glu Leu Glu His Ile Ile Trp Thr Leu Phe Gln His Thr Leu 675 680 685 Gln Asn Glu Tyr Glu Leu Met Arg Asp Arg His Leu Asp Gln Ile Met 690 695 700 Met Cys Ser Met Tyr Gly Ile Cys Lys Val Lys Asn Ile Asp Leu Lys 705 710 715 720 Phe Lys Ile Ile Val Thr Ala Tyr Lys Asp Leu Pro His Ala Val Gln 725 730 735 Glu Thr Phe Lys Arg Val Leu Ile Lys Glu Glu Glu Tyr Asp Ser Ile 740 745 750 Ile Val Phe Tyr Asn Ser Val Phe Met Gln Arg Leu Lys Thr Asn Ile 755 760 765 Leu Gln Tyr Ala Ser Thr Arg Pro Pro Thr Leu Ser Pro Ile Pro His 770 775 780 Ile Pro Arg Ser Pro Tyr Lys Phe Pro Ser Ser Pro Leu Arg Ile Pro 785 790 795 800 Gly Gly Asn Ile Tyr Ile Ser Pro Leu Lys Ser Pro Tyr Lys Ile Ser 805 810 815 Glu Gly Leu Pro Thr Pro Thr Lys Met Thr Pro Arg Ser Arg Ile Leu 820 825 830 Val Ser Ile Gly Glu Ser Phe Gly Thr Ser Glu Lys Phe Gln Lys Ile 835 840 845 Asn Gln Met Val Cys Asn Ser Asp Arg Val Leu Lys Arg Ser Ala Glu 850 855 860 Gly Ser Asn Pro Pro Lys Pro Leu Lys Lys Leu Arg Phe Asp Ile Glu 865 870 875 880 Gly Ser Asp Glu Ala Asp Gly Ser Lys His Leu Pro Gly Glu Ser Lys 885 890 895 Phe Gln Gln Lys Leu Ala Glu Met Thr Ser Thr Arg Thr Arg Met Gln 900 905 910 Lys Gln Lys Met Asn Asp Ser Met Asp Thr Ser Asn Lys Glu Glu Lys 915 920 925 <110> Industry-Academic Cooperation Foundation, Yonsei University <120> Prostate cancer subtype classification method and classification apparatus <130> PDPB204208 <160> 12 <170> KoPatentIn 3.0 <210> 1 <211> 374 <212> PRT <213> Homo sapiens <400> 1 Met Ser Arg Val Pro Ser Pro Pro Pro Pro Ala Glu Met Ser Ser Gly 1 5 10 15 Pro Val Ala Glu Ser Trp Cys Tyr Thr Gln Ile Lys Val Val Lys Phe 20 25 30 Ser Tyr Met Trp Thr Ile Asn Asn Phe Ser Phe Cys Arg Glu Glu Met 35 40 45 Gly Glu Val Ile Lys Ser Ser Thr Phe Ser Ser Gly Ala Asn Asp Lys 50 55 60 Leu Lys Trp Cys Leu Arg Val Asn Pro Lys Gly Leu Asp Glu Glu Ser 65 70 75 80 Lys Asp Tyr Leu Ser Leu Tyr Leu Leu Leu Val Ser Cys Pro Lys Ser 85 90 95 Glu Val Arg Ala Lys Phe Lys Phe Ser Ile Leu Asn Ala Lys Gly Glu 100 105 110 Glu Thr Lys Ala Met Glu Ser Gln Arg Ala Tyr Arg Phe Val Gln Gly 115 120 125 Lys Asp Trp Gly Phe Lys Lys Phe Ile Arg Arg Asp Phe Leu Leu Asp 130 135 140 Glu Ala Asn Gly Leu Leu Pro Asp Asp Lys Leu Thr Leu Phe Cys Glu 145 150 155 160 Val Ser Val Val Gln Asp Ser Val Asn Ile Ser Gly Gln Asn Thr Met 165 170 175 Asn Met Val Lys Val Pro Glu Cys Arg Leu Ala Asp Glu Leu Gly Gly 180 185 190 Leu Trp Glu Asn Ser Arg Phe Thr Asp Cys Cys Leu Cys Val Ala Gly 195 200 205 Gln Glu Phe Gln Ala His Lys Ala Ile Leu Ala Ala Arg Ser Pro Val 210 215 220 Phe Ser Ala Met Phe Glu His Glu Met Glu Glu Ser Lys Lys Asn Arg 225 230 235 240 Val Glu Ile Asn Asp Val Glu Pro Glu Val Phe Lys Glu Met Met Cys 245 250 255 Phe Ile Tyr Thr Gly Lys Ala Pro Asn Leu Asp Lys Met Ala Asp Asp 260 265 270 Leu Leu Ala Ala Ala Asp Lys Tyr Ala Leu Glu Arg Leu Lys Val Met 275 280 285 Cys Glu Asp Ala Leu Cys Ser Asn Leu Ser Val Glu Asn Ala Ala Glu 290 295 300 Ile Leu Ile Leu Ala Asp Leu His Ser Ala Asp Gln Leu Lys Thr Gln 305 310 315 320 Ala Val Asp Phe Ile Asn Tyr His Ala Ser Asp Val Leu Glu Thr Ser 325 330 335 Gly Trp Lys Ser Met Val Val Ser His Pro His Leu Val Ala Glu Ala 340 345 350 Tyr Arg Ser Leu Ala Ser Ala Gln Cys Pro Phe Leu Gly Pro Pro Arg 355 360 365 Lys Arg Leu Lys Gln Ser 370 <210> 2 <211> 825 <212> PRT <213> Homo sapiens <400> 2 Met Leu Asp Ile Cys Leu Glu Lys Arg Val Gly Thr Thr Leu Ala Ala 1 5 10 15 Pro Lys Cys Asn Ser Ser Thr Val Arg Phe Gln Gly Leu Ala Glu Gly 20 25 30 Thr Lys Gly Thr Met Lys Met Asp Met Glu Asp Ala Asp Met Thr Leu 35 40 45 Trp Thr Glu Ala Glu Phe Glu Glu Lys Cys Thr Tyr Ile Val Asn Asp 50 55 60 His Pro T rp Asp Ser Gly Ala Asp Gly Gly Thr Ser Val Gln Ala Glu 65 70 75 80 Ala Ser Leu Pro Arg Asn Leu Leu Phe Lys Tyr Ala Thr Asn Ser Glu 85 90 95 Glu Val Ile Gly Val Met Ser Lys Glu Tyr Ile Pro Lys Gly Thr Arg 100 105 110 Phe Gly Pro Leu Ile Gly Glu Ile Tyr Thr Asn Asp Thr Val Pro Lys 115 120 125 Asn Ala Asn Arg Lys Tyr Phe Trp Arg Ile Tyr Ser Arg Gly Glu Leu 130 135 140 His His Phe Ile Asp Gly Phe Asn Glu Glu Lys Ser Asn Trp Met Arg 145 150 155 160 Tyr Val Asn Pro Ala His Ser Pro Arg Glu Gln Asn Leu Ala Ala Cys 165 170 175 Gln Asn Gly Met Asn Ile Tyr Phe Tyr Thr Ile Lys Pro Ile Pro Ala 180 185 190 Asn Gln Glu Leu Leu Val Trp Tyr Cys Arg Asp Phe Ala Glu Arg Leu 195 200 205 His Tyr Pro Tyr Pro Gly Glu Leu Thr Met Met Asn Leu Thr Gln Thr 210 215 220 Gln Ser Ser Leu Lys Gln Pro Ser Thr Glu Lys Asn Glu Leu Cys Pro 225 230 235 240 Lys Asn Val Pro Lys Arg Glu Tyr Ser Val Lys Glu Ile Leu Lys Leu 245 250 255 Asp Ser Asn Pro Ser Lys Gly Lys Asp Leu Tyr Arg Ser Asn Ile Ser 260 265 270 Pro Leu Thr Ser Glu Lys Asp Leu Asp Asp Phe Arg Arg Arg Gly Ser 275 280 285 Pro Glu Met Pro Phe Tyr Pro Arg Val Val Tyr Pro Ile Arg Ala Pro 290 295 300 Leu Pro Glu Asp Phe Leu Lys Ala Ser Leu Ala Tyr Gly Ile Glu Arg 305 310 315 320 Pro Thr Tyr Ile Thr Arg Ser Pro Ile Pro Ser Ser Thr Thr Pro Ser 325 330 335 Pro Ser Ala Arg Ser Ser Pro Asp Gln Ser Leu Lys Ser Ser Ser Pro 340 345 350 His Ser Ser Pro Gly Asn Thr Val Ser Pro Val Gly Pro Gly Ser Gln 355 360 365 Glu His Arg Asp Ser Tyr Ala Tyr Leu Asn Ala Ser Tyr Gly Thr Glu 370 375 380 Gly Leu Gly Ser Tyr Pro Gly Tyr Ala Pro Leu Pro His Leu Pro Pro 385 390 395 400 Ala Phe Ile Pro Ser Tyr Asn Ala His Tyr Pro Lys Phe Leu Leu Pro 405 410 415 Pro Tyr Gly Met Asn Cys Asn Gly Leu Ser Ala Val Ser Ser Met Asn 420 425 430 Gly Ile Asn Asn Phe Gly Leu Phe Pro Arg Leu Cys Pro Val Tyr Ser 435 440 445 Asn Leu Leu Gly Gly Gly Ser Leu Pro His Pro Met Leu Asn Pro Thr 450 455 460 Ser Leu Pro Ser Ser Leu Pro Ser Asp Gly Ala Arg Arg Leu Leu Gln 465 470 475 480 Pro Glu His Pro Arg Glu Val Leu Val Pro Ala Pro His Ser Ala Phe 485 490 495 Ser Phe Thr Gly Ala Ala Ala Ser Met Lys Asp Lys Ala Cys Ser Pro 500 505 510 Thr Ser Gly Ser Pro Thr Ala Gly Thr Ala Ala Thr Ala Glu His Val 515 520 525 Val Gln Pro Lys Ala Thr Ser Ala Ala Met Ala Ala Pro Ser Ser Asp 530 535 540 Glu Ala Met Asn Leu Ile Lys Asn Lys Arg Asn Met Thr Gly Tyr Lys 545 550 555 560 Thr Leu Pro Tyr Pro Leu Lys Lys Gln Asn Gly Lys Ile Lys Tyr Glu 565 570 575 Cys Asn Val Cys Ala Lys Thr Phe Gly Gln Leu Ser Asn Leu Lys Val 580 585 590 His Leu Arg Val His Ser Gly Glu Arg Pro Phe Lys Cys Gln Thr Cys 595 600 605 Asn Lys Gly Phe Thr Gln Leu Ala His Leu Gln Lys His Tyr Leu Val 610 615 620 His Thr Gly Glu Lys Pro His Glu Cys Gln Val Cys His Lys Arg Phe 625 630 635 640 Ser Ser Thr Ser Asn Leu Lys Thr His Leu Arg Leu His Ser Gly Glu 645 650 655 Lys Pro Tyr Gln Cys Lys Val Cys Pro Ala Lys Phe Thr Gln Phe Val 660 665 670 His Leu Lys Leu His Lys Arg Leu His Thr Arg Glu Arg Pro His Lys 675 680 685 Cys Ser Gln Cys His Lys Asn Tyr Ile His Leu Cys Ser Leu Lys Val 690 695 700 His Leu Lys Gly Asn Cys Ala Ala Ala Pro Ala Pro Gly Leu Pro Leu 705 710 715 720 Glu Asp Leu Thr Arg Ile Asn Glu Glu Ile Glu Lys Phe Asp Ile Ser 725 730 735 Asp Asn Ala Asp Arg Leu Glu Asp Val Glu Asp Asp Ile Ser Val Ile 740 745 750 Ser Val Val Glu Lys Glu Ile Leu Ala Val Val Arg Lys Glu Lys Glu 755 760 765 Glu Thr Gly Leu Lys Val Ser Leu Gln Arg Asn Met Gly Asn Gly Leu 770 775 780 Leu Ser Ser Gly Cys Ser Leu Tyr Glu Ser Ser Asp Leu Pro Leu Met 785 790 795 800 Lys Leu Pro Pro Ser Asn Pro Leu Pro Leu Val Pro Val Lys Val Lys 805 810 815 Gln Glu Thr Val Glu Pro Met Asp Pro 820 825 <210> 3 <211> 479 <212> PRT <213 > Homo sapiens <400> 3 Met Ala Ser Thr Ile Lys Glu Ala Leu Ser Val Val Ser Glu Asp Gln 1 5 10 15 Ser Leu Phe Glu Cys Ala Tyr Gly Thr Pro His Leu Ala Lys Thr Glu 20 25 30 Met Thr Ala Ser Ser Ser Ser Asp Tyr Gly Gln Thr Ser Lys Met Ser 35 40 45 Pro Arg Val Pro Gln Gln Asp Trp Leu Ser Gln Pro Pro Ala Arg Val 50 55 60 Thr Ile Lys Met Glu Cys Asn Pro Ser Gln Val Asn Gly Ser Arg Asn 65 70 75 80 Ser Pro Asp Glu Cys Ser Val Ala Lys Gly Gly Lys Met Val Gly Ser 85 90 95 Pro Asp Thr Val Gly Met Asn Tyr Gly Ser Tyr Met Glu Glu Lys His 100 105 110 Met Pro Pro Pro Asn Met Thr Thr Asn Glu Arg Arg Val Ile Val Pro 115 120 125 Ala Asp Pro Thr Leu Trp Ser Thr A sp His Val Arg Gln Trp Leu Glu 130 135 140 Trp Ala Val Lys Glu Tyr Gly Leu Pro Asp Val Asn Ile Leu Leu Phe 145 150 155 160 Gln Asn Ile Asp Gly Lys Glu Leu Cys Lys Met Thr Lys Asp Asp Phe 165 170 175 Gln Arg Leu Thr Pro Ser Tyr Asn Ala Asp Ile Leu Leu Ser His Leu 180 185 190 His Tyr Leu Arg Glu Thr Pro Leu Pro His Leu Thr Ser Asp Asp Val 195 200 205 Asp Lys Ala Leu Gln Asn Ser Pro Arg Leu Met His Ala Arg Asn Thr 210 215 220 Gly Gly Ala Ala Phe Ile Phe Pro Asn Thr Ser Val Tyr Pro Glu Ala 225 230 235 240 Thr Gln Arg Ile Thr Thr Arg Pro Asp Leu Pro Tyr Glu Pro Arg 245 250 255 Arg Ser Ala Trp Thr Gly His Gly His Pro Thr Pro Gln Ser Lys Ala 260 265 270 Ala Gln Pro Ser Pro S er Thr Val Pro Lys Thr Glu Asp Gln Arg Pro 275 280 285 Gln Leu Asp Pro Tyr Gln Ile Leu Gly Pro Thr Ser Ser Arg Leu Ala 290 295 300 Asn Pro Gly Ser Gly Gln Ile Gln Leu Trp Gln Phe Leu Leu Glu Leu 305 310 315 320 Leu Ser Asp Ser Ser Asn Ser Ser Cys Ile Thr Trp Glu Gly Thr Asn 325 330 335 Gly Glu Phe Lys Met Thr Asp Pro Asp Glu Val Ala Arg Arg Trp Gly 340 345 350 Glu Arg Lys Ser Lys Pro Asn Met Asn Tyr Asp Lys Leu Ser Arg Ala 355 360 365 Leu Arg Tyr Tyr Tyr Asp Lys Asn Ile Met Thr Lys Val His Gly Lys 370 375 380 Arg Tyr Ala Tyr Lys Phe Asp Phe His Gly Ile Ala Gln Ala Leu Gln 385 390 395 400 Pro His Pro Pro Glu Ser Ser Leu Tyr Lys Tyr Pro Ser Asp Leu Pro 405 410 415 Tyr Met G ly Ser Tyr His Ala His Pro Gln Lys Met Asn Phe Val Ala 420 425 430 Pro His Pro Pro Ala Leu Pro Val Thr Ser Ser Ser Phe Phe Ala Ala 435 440 445 Pro Asn Pro Tyr Trp Asn Ser Pro Thr Gly Gly Ile Tyr Pro Asn Thr 450 455 460 Arg Leu Pro Thr Ser His Met Pro Ser His Leu Gly Thr Tyr Tyr 465 470 475 <210> 4 <211> 477 <212> PRT <213> Homo sapiens <400> 4 Met Asp Gly Phe Tyr Asp Gln Gln Val Pro Tyr Met Val Thr Asn Ser 1 5 10 15 Gln Arg Gly Arg Asn Cys Asn Glu Lys Pro Thr Asn Val Arg Lys Arg 20 25 30 Lys Phe Ile Asn Arg Asp Leu Ala His Asp Ser Glu Glu Leu Phe Gln 35 40 45 Asp Leu Ser Gln Leu Gln Glu Thr Trp Leu Ala Glu Ala Gln Val Pro 50 55 60 Asp Asn Asp Glu Gln Phe Val Pro Asp Tyr Gln Ala Glu Ser Leu Ala 65 70 75 80 Phe His Gly Leu Pro Leu Lys Ile Lys Lys Glu Pro His Ser Pro Cys 85 90 95 Ser Glu Ile Ser Ser Ala Cys Ser Gln Glu Gln Pro Phe Lys Phe Ser 100 105 110 Tyr Gly Glu Lys Cys Leu Tyr Asn Val Ser Ala Tyr Asp Gln Lys Pro 115 120 125 Gln Val Gly Met Arg Pro Ser Asn Pro Pro Thr Pro Ser Ser Thr Pro 130 135 140 Val Ser Pro Leu His His Ala Ser Pro Asn Ser Thr His Thr Pro Lys 145 150 155 160 Pro Asp Arg Ala Phe Pro Ala His Leu Pro Pro Ser Gln Ser Ile Pro 165 170 175 Asp Ser Ser Tyr Pro Met Asp His Arg Phe Arg Arg Gln Leu Ser Glu 180 185 190 Pro Cys Asn Ser Phe Pro Pro Leu Pro Thr Met Pro Arg Glu Gly Arg 195 200 205 Pro Met Tyr Gln Arg Gln Met Ser Glu Pro Asn Ile Pro Phe Pro Pro 210 215 220 Gln Gly Phe Lys Gln Glu Tyr His Asp Pro Val Tyr Glu His Asn Thr 225 230 235 240 Met Val Gly Ser Ala Ala Ser Gln Ser Phe Pro Pro Leu Me t Ile 245 250 255 Lys Gln Glu Pro Arg Asp Phe Ala Tyr Asp Ser Glu Val Pro Ser Cys 260 265 270 His Ser Ile Tyr Met Arg Gln Glu Gly Phe Leu Ala His Pro Ser Arg 275 280 285 Thr Glu Gly Cys Met Phe Glu Lys Gly Pro Arg Gln Phe Tyr Asp Asp 290 295 300 Thr Cys Val Val Pro Glu Lys Phe Asp Gly Asp Ile Lys Gln Glu Pro 305 310 315 320 Gly Met Tyr Arg Glu Gly Pro Thr Tyr Gln Arg Arg Gly Ser Leu Gln 325 330 335 Leu Trp Gln Phe Leu Val Ala Leu Leu Asp Asp Pro Ser Asn Ser His 340 345 350 Phe Ile Ala Trp Thr Gly Arg Gly Met Glu Phe Lys Leu Ile Glu Pro 355 360 365 Glu Glu Val Ala Arg Arg Trp Gly Ile Gln Lys Asn Arg Pro Ala Met 370 375 380 Asn Tyr Asp Lys Leu Ser Arg Ser Leu Arg Tyr Tyr Tyr Glu Lys Gly 38 5 390 395 400 Ile Met Gln Lys Val Ala Gly Glu Arg Tyr Val Tyr Lys Phe Val Cys 405 410 415 Asp Pro Glu Ala Leu Phe Ser Met Ala Phe Pro Asp Asn Gln Arg Pro 420 425 430 Leu Leu Lys Thr Asp Met Glu Arg His Ile Asn Glu Glu Asp Thr Val 435 440 445 Pro Leu Ser His Phe Asp Glu Ser Met Ala Tyr Met Pro Glu Gly Gly 450 455 460 Cys Cys Asn Pro His Pro Tyr Asn Glu Gly Tyr Val Tyr 465 470 475 <210> 5 <211> 484 <212> PRT <213> Homo sapiens <400> 5 Met Glu Arg Arg Met Lys Ala Gly Tyr Leu Asp Gln Gln Val Pro Tyr 1 5 10 15 Thr Phe Ser Ser Lys Ser Pro Gly Asn Gly Ser Leu Arg Glu Ala Leu 20 25 30 Ile Gly Pro Leu Gly Lys Leu Met Asp Pro Gly Ser Leu Pro Pro Leu 35 40 45 Asp Ser Glu Asp Leu Phe Gln Asp Leu Ser His Phe Gln Glu Thr Trp 50 55 60 Leu Ala Glu Ala Gln Val Pro Asp Ser Asp Glu Gln Phe Val Pro Asp 65 70 75 80 Phe His Ser Glu Asn Leu Ala Phe His Ser Pro Thr Thr Arg Ile Lys 85 90 95 Lys Glu Pro Gln Ser Pro Arg Thr Asp Pro Ala Leu Ser Cys Ser Arg 100 105 110 Lys Pro Pro Leu Pro Tyr His His Gly Glu Gln Cys Leu Tyr Ser Ser 115 120 125 Ala Tyr Asp Pro Pro Arg Gln Ile Ala Ile Lys Ser Pro Ala Pro Gly 130 135 140 Ala Leu Gly Gln Ser Pro Leu Gln Pro Phe Pro Arg Ala Glu Gln Arg 145 150 155 160 Asn Phe Leu Arg Ser Ser Gly Thr Ser Gln Pro His Pro Gly His Gly 165 170 175 Tyr Leu Gly Glu His Ser Ser Val Phe Gln Gln Pro Leu Asp Ile Cys 180 185 190 His Ser Phe Thr Ser Gln Gly Gly Gly Arg Glu Pro Leu Pro Ala Pro 195 200 205 Tyr Gln His Gln Leu Ser Glu Pro Cys Pro Pro Tyr Pro Gln Gln Ser 210 215 220 Phe Lys Gln Glu Tyr His Asp Pro Leu Tyr Glu Gln Ala Gly Gln Pro 225 230 235 240 Ala Val Asp Gln Gly Gly Val Asn Gly His Arg Tyr Pro Gly Ala Gly 245 250 255 Val Val Ile Lys Gln Glu Gln Thr Asp Phe Ala Tyr Asp Ser Asp Val 260 265 270 Thr Gly Cys Ala Ser Met Tyr Leu His Thr Glu Gly Phe Ser Gly Pro 275 280 285 Ser Pro Gly Asp Gly Ala Met Gly Tyr Gly Tyr Glu Lys Pro Leu Arg 290 295 300 Pro Phe Pro Asp Asp Val Cys Val Val Pro Glu Lys Phe Glu Gly Asp 305 310 315 320 Ile Lys Gln Glu Gly Val Gly Ala Phe Arg Glu Gly Pro Tyr Gln 325 330 335 Arg Arg Gly Ala Leu Gln Leu Trp Gln Phe Leu Val Ala Leu Leu Asp 340 345 350 Asp Pro Thr Asn Ala His Phe Ile Ala Trp Thr Gly Arg Gly Met Glu 355 360 365 Phe Lys Leu Ile Glu Pro Glu Glu Val Ala Arg Leu Trp Gly Ile Gln 370 375 380 Lys Asn Arg Pro Ala Met Asn Tyr Asp Lys Leu Ser Arg Ser Leu Arg 385 390 395 400 Tyr Tyr Tyr Glu Lys Gly Ile Met Gln Lys Val Ala Gly Glu Arg Tyr 405 410 415 Val Tyr Lys Phe Val Cys Glu Pro Glu Ala Leu Phe Ser Leu Ala Phe 420 425 430 Pro Asp Asn Gln Arg Pro Ala Leu Lys Ala Glu Phe Asp Arg Pro Val 435 440 445 Ser Glu Glu Asp Thr Val Pro Leu Ser His Leu Asp Glu Ser Pro Ala 450 455 460 Tyr Leu Pro Glu Leu Ala Gly Pro Ala Gln Pro Phe Gly Pro Lys Gly 465 470 475 480 Gly Tyr Ser Tyr <210> 6 <211> 510 <212> PRT <213> Homo sapiens <400> 6 Met Asp Gly Phe Tyr Asp Gln Gln Val Pro Phe Met Val Pro Gly Lys 1 5 10 15 Ser Arg Ser Glu Glu Cys Arg Gly Arg Pro Val Ile Asp Arg Lys Arg 20 25 30 Lys Phe Leu Asp Thr Asp Leu Ala His Asp Ser Glu Glu Leu Phe Gln 35 40 45 Asp Leu Ser Gln Leu Gln Glu Ala Trp Leu Ala Glu Ala Gln Val Pro 50 55 60 Asp Asp Glu Gln Phe Val Pro Asp Phe Gln Ser Asp As n Leu Val Leu 65 70 75 80 His Ala Pro Pro Pro Thr Lys Ile Lys Arg Glu Leu His Ser Pro Ser 85 90 95 Ser Glu Leu Ser Ser Cys Ser His Glu Gln Ala Leu Gly Ala Asn Tyr 100 105 110 Gly Glu Lys Cys Leu Tyr Asn Tyr Cys Ala Tyr Asp Arg Lys Pro Pro 115 120 125 Ser Gly Phe Lys Pro Leu Thr Pro Pro Thr Thr Pro Leu Ser Pro Thr 130 135 140 His Gln Asn Pro Leu Phe Pro Pro Pro Gln Ala Thr Leu Pro Thr Ser 145 150 155 160 Gly His Ala Pro Ala Ala Gly Pro Val Gln Gly Val Gly Pro Ala Pro 165 170 175 Ala Pro His Ser Leu Pro Glu Pro Gly Pro Gln Gln Gln Thr Phe Ala 180 185 190 Val Pro Arg Pro Pro His Gln Pro Leu Gln Met Pro Lys Met Met Pro 195 200 205 Glu Asn Gln Tyr Pro Ser Glu Gln Arg Phe Gln Arg Gln Leu Ser Glu 210 215 220 Pro Cys His Pro P he Pro Pro Gln Pro Gly Val Pro Gly Asp Asn Arg 225 230 235 240 Pro Ser Tyr His Arg Gln Met Ser Glu Pro Ile Val Pro Ala Ala Pro 245 250 255 Pro Pro Pro Gln Gly Phe Lys Gln Glu Tyr His Asp Pro Leu Tyr Glu 260 265 270 His Gly Val Pro Gly Met Pro Gly Pro Pro Ala His Gly Phe Gln Ser 275 280 285 Pro Met Gly Ile Lys Gln Glu Pro Arg Asp Tyr Cys Val Asp Ser Glu 290 295 300 Val Pro Asn Cys Gln Ser Ser Tyr Met Arg Gly Gly Tyr Phe Ser Ser 305 310 315 320 Ser His Glu Gly Phe Ser Tyr Glu Lys Asp Pro Arg Leu Tyr Phe Asp 325 330 335 Asp Thr Cys Val Val Pro Glu Arg Leu Glu Gly Lys Val Lys Gln Glu 340 345 350 Pro Thr Met Tyr Arg Glu Gly Pro Pro Tyr Gln Arg Arg Gly Ser Leu 355 360 365 Gln L eu Trp Gln Phe Leu Val Thr Leu Leu Asp Asp Pro Ala Asn Ala 370 375 380 His Phe Ile Ala Trp Thr Gly Arg Gly Met Glu Phe Lys Leu Ile Glu 385 390 395 400 Pro Glu Glu Val Ala Arg Arg Trp Gly Ile Gln Lys Asn Arg Pro Ala 405 410 415 Met Asn Tyr Asp Lys Leu Ser Arg Ser Leu Arg Tyr Tyr Tyr Glu Lys 420 425 430 Gly Ile Met Gln Lys Val Ala Gly Glu Arg Tyr Val Tyr Lys Phe Val 435 440 445 Cys Asp Pro Asp Ala Leu Phe Ser Met Ala Phe Pro Asp Asn Gln Arg 450 455 460 Pro Phe Leu Lys Ala Glu Ser Glu Cys His Leu Ser Glu Glu Asp Thr 465 470 475 480 Leu Pro Leu Thr His Phe Glu Asp Ser Pro Ala Tyr Leu Leu Asp Met 485 490 495 Asp Arg Cys Ser Ser Leu Pro Tyr Ala Glu Gly Phe Ala Tyr 500 505 510 < 210> 7 <211> 452 <212> PRT <213> Homo sapiens <400> 7 Met Ser Glu Thr Pro Ala Gln Cys Ser Ile Lys Gln Glu Arg Ile Ser 1 5 10 15 Tyr Thr Pro Pro Glu Ser Pro Val Pro Ser Tyr Ala Ser Ser Thr Pro 20 25 30 Leu His Val Pro Val Pro Arg Ala Leu Arg Met Glu Glu Asp Ser Ile 35 40 45 Arg Leu Pro Ala His Leu Arg Leu Gln Pro Ile Tyr Trp Ser Arg Asp 50 55 60 Asp Val Ala Gln Trp Leu Lys Trp Ala Glu Asn Glu Phe Ser Leu Arg 65 70 75 80 Pro Ile Asp Ser Asn Thr Phe Glu Met Asn Gly Lys Ala Leu Leu Leu 85 90 95 Leu Thr Lys Glu Asp Phe Arg Tyr Arg Ser Pro His Ser Gly Asp Val 100 105 110 Leu Tyr Glu Leu Leu Gln His Ile Leu Lys Gln Arg Lys Pro Arg Ile 115 120 125 Leu Phe Ser Pro Phe Phe His Pro Gly Asn Ser Ile His Thr Gln Pro 130 135 140 Glu Val Ile Leu His Gln Asn His Glu Glu Asp Asn Cys Val Gln Arg 145 150 155 160 Thr Pro Arg Pro Ser Val Asp Asn Val Hi s His Asn Pro Pro Thr Ile 165 170 175 Glu Leu Leu His Arg Ser Arg Ser Pro Ile Thr Thr Asn His Arg Pro 180 185 190 Ser Pro Asp Pro Glu Gln Arg Pro Leu Arg Ser Pro Leu Asp Asn Met 195 200 205 Ile Arg Arg Leu Ser Pro Ala Glu Arg Ala Gln Gly Pro Arg Pro His 210 215 220 Gln Glu Asn Asn His Gln Glu Ser Tyr Pro Leu Ser Val Ser Pro Met 225 230 235 240 Glu Asn Asn His Cys Pro Ala Ser Ser Glu Ser His Pro Lys Pro Ser 245 250 255 Ser Pro Arg Gln Glu Ser Thr Arg Val Ile Gln Leu Met Pro Ser Pro 260 265 270 Ile Met His Pro Leu Ile Leu Asn Pro Arg His Ser Val Asp Phe Lys 275 280 285 Gln Ser Arg Leu Ser Glu Asp Gly Leu His Arg Glu Gly Lys Pro Ile 290 295 300 Asn Leu Ser His Arg Glu Asp Leu Ala Tyr Met As n His Ile Met Val 305 310 315 320 Ser Val Ser Pro Pro Glu Glu His Ala Met Pro Ile Gly Arg Ile Ala 325 330 335 Asp Cys Arg Leu Leu Trp Asp Tyr Val Tyr Gln Leu Leu Ser Asp Ser 340 345 350 Arg Tyr Glu Asn Phe Ile Arg Trp Glu Asp Lys Glu Ser Lys Ile Phe 355 360 365 Arg Ile Val Asp Pro Asn Gly Leu Ala Arg Leu Trp Gly Asn His Lys 370 375 380 Asn Arg Thr Asn Met Thr Tyr Glu Lys Met Ser Arg Ala Leu Arg His 385 390 395 400 Tyr Tyr Lys Leu Asn Ile Ile Arg Lys Glu Pro Gly Gln Arg Leu Leu 405 410 415 Phe Arg Phe Met Lys Thr Pro Asp Glu Ile Met Ser Gly Arg Thr Asp 420 425 430 Arg Leu Glu His Leu Glu Ser Gln Glu Leu Asp Glu Gln Ile Tyr Gln 435 440 445 Glu Asp Glu Cys 450 <210> 8 <211> 403 <212> PRT <213> Homo sapiens <400> 8 Met Thr Ala Ile Ile Lys Glu Ile Val Ser Arg Asn Lys Arg Arg Tyr 1 5 10 15 Gln Glu Asp Gly Phe Asp Leu Asp Leu Thr Tyr Ile Tyr Pro Asn Ile 20 25 30 Ile Ala Met Gly Phe Pro Ala Glu Arg Leu Glu Gly Val Tyr Arg Asn 35 40 45 Asn Ile Asp Asp Val Val Arg Phe Leu Asp Ser Lys His Lys Asn His 50 55 60 Tyr Lys Ile Tyr Asn Leu Cys Ala Glu Arg His Tyr Asp Thr Ala Lys 65 70 75 80 Phe Asn Cys Arg Val Ala Gln Tyr Pro Phe Glu Asp His Asn Pro Pro 85 90 95 Gln Leu Glu Leu Ile Lys Pro Phe Cys Glu Asp Leu Asp Gln Trp Leu 100 105 110 Ser Glu Asp Asp Asn His Val Ala Ala Ile His Cys Lys Ala Gly Lys 115 120 125 Gly Arg Thr Gly Val Met Ile Cys Ala Tyr Leu Leu His Arg Gly Lys 130 135 140 Phe Leu Lys Ala Gln Glu Ala Leu Asp Glu Phe Tyr Gly Glu Val Arg Thr 145 150 155 160 Arg Asp Lys Lys Gly Val Thr Ile Pro Ser Gln Arg Arg Tyr Val Tyr 165 170 175 Tyr Tyr Ser Tyr Leu Leu Lys Asn His Leu Asp Tyr Arg Pro Val Ala 180 185 190 Leu Leu Phe His Lys Met Met Phe Glu Thr Ile Pro Met Phe Ser Gly 195 200 205 Gly Thr Cys Asn Pro Gln Phe Val Val Cys Gln Leu Lys Val Lys Ile 210 215 220 Tyr Ser Ser Asn Ser Gly Pro Thr Arg Arg Glu Asp Lys Phe Met Tyr 225 230 235 240 Phe Glu Phe Pro Gln Pro Leu Pro Val Cys Gly Asp Ile Lys Val Glu 245 250 255 Phe Phe His Lys Gln Asn Lys Met Leu Lys Lys Asp Lys Met Phe His 260 265 270 Phe Trp Val Asn Thr Phe Phe Ile Pro Gly Pro Glu Glu Thr Ser Glu 275 280 285 Lys Val Glu Asn Gly Ser Leu Cys Asp Gln Glu Ile Asp Ser Ile Cys 290 295 300 Ser Ile Glu Arg Ala Asp Asn Asp Lys Glu Tyr Leu Val Leu Thr Leu 305 310 315 320 Thr Lys Asn Asp Leu Asp Lys Ala Asn Lys Asp Lys Ala Asn Arg Tyr 325 330 335 Phe Ser Pro Asn Phe Lys Val Lys Leu Tyr Phe Thr Lys Thr Val Glu 340 345 350 Glu Pro Ser Asn Pro Glu Ala Ser Ser Ser Thr Ser Val Thr Pro Asp 355 360 365 Val Ser Asp Asn Glu Pro Asp His Tyr Arg Tyr Ser Asp Thr Thr Asp 370 375 380 Ser Asp Pro Glu Asn Glu Pro Phe Asp Glu Asp Gln His Thr Gln Ile 385 390 395 400 Thr Lys Val <210> 9 <211> 393 <212> PRT <213> Homo sapiens <400> 9 Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln 1 5 10 15 Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu 20 25 30 Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp 35 40 45 Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro 50 55 60 Arg Met Pro Glu Ala Ala Pro Val Ala Pro Ala Pro Ala Ala Pro 65 70 75 80 Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser 85 90 95 Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly 100 105 110 Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro 115 120 125 Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln 130 135 140 Leu Trp Val Asp Ser Thr Pro Pro Gly Thr Arg Val Arg Ala Met 145 150 155 160 Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys 165 170 175 Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln 180 185 190 His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp 195 200 205 Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu 210 215 220 Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser 225 230 235 240 Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr 245 250 255 Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val 260 265 270 Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn 275 280 285 Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr 290 295 300 Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys 305 310 315 320 Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu 325 330 335 Arg Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp 340 345 350 Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His 355 360 365 Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met 370 375 380 Phe Lys Thr Glu Gly Pro Asp Ser Asp 385 390 <210> 10 <211> 1068 <212> PRT <213> Homo sapiens <400> 10 Met Pro Pro Arg Pro Ser Ser Gly Glu Leu Trp Gly Ile His Leu Met 1 5 10 15 Pro Pro Arg Ile Leu Val Glu Cys Leu Leu Pro Asn Gly Met Ile Val 20 25 30 Thr Leu Glu Cys Leu Arg Glu Ala Thr Leu Ile Thr Ile Lys His Glu 35 40 45 Leu Phe Lys Glu Ala Arg Lys Tyr Pro Leu His Gln Leu Leu Gln Asp 50 55 60 Glu Ser Ser Tyr Ile Phe Val Ser Val Thr Gln Glu Ala Glu Arg Glu 65 70 75 80 Glu Phe Phe Asp Glu Thr Arg Arg Leu Cys Asp Leu Arg Leu Phe Gln 85 90 95 Pro Phe Leu Lys Val Ile Glu Pro Val Gly Asn Arg Glu Glu Lys Ile 100 105 110 Leu Asn Arg Glu Ile Gly Phe Ala Ile Gly Met Pro Val Cys Glu Phe 115 120 125 Asp Met Val Lys Asp Pro Glu Val Gln Asp Phe Arg Arg As n Ile Leu 130 135 140 Asn Val Cys Lys Glu Ala Val Asp Leu Arg Asp Leu Asn Ser Pro His 145 150 155 160 Ser Arg Ala Met Tyr Val Tyr Pro Pro Asn Val Glu Ser Ser Pro Glu 165 170 175 Leu Pro Lys His Ile Tyr Asn Lys Leu Asp Lys Gly Gln Ile Ile Val 180 185 190 Val Ile Trp Val Ile Val Ser Pro Asn Asn Asp Lys Gln Lys Tyr Thr 195 200 205 Leu Lys Ile Asn His Asp Cys Val Pro Glu Gln Val Ile Ala Glu Ala 210 215 220 Ile Arg Lys Lys Thr Arg Ser Met Leu Leu Ser Ser Glu Gln Leu Lys 225 230 235 240 Leu Cys Val Leu Glu Tyr Gln Gly Lys Tyr Ile Leu Lys Val Cys Gly 245 250 255 Cys Asp Glu Tyr Phe Leu Glu Lys Tyr Pro Leu Ser Gln Tyr Lys Tyr 260 265 270 Ile Arg Ser Cys Ile Met Leu Gly Arg Met Pr o Asn Leu Met Leu Met 275 280 285 Ala Lys Glu Ser Leu Tyr Ser Gln Leu Pro Met Asp Cys Phe Thr Met 290 295 300 Pro Ser Tyr Ser Arg Arg Ile Ser Thr Ala Thr Pro Tyr Met Asn Gly 305 310 315 320 Glu Thr Ser Thr Lys Ser Leu Trp Val Ile Asn Ser Ala Leu Arg Ile 325 330 335 Lys Ile Leu Cys Ala Thr Tyr Val Asn Val Asn Ile Arg Asp Ile Asp 340 345 350 Lys Ile Tyr Val Arg Thr Gly Ile Tyr His Gly Gly Glu Pro Leu Cys 355 360 365 Asp Asn Val Asn Thr Gln Arg Val Pro Cys Ser Asn Pro Arg Trp Asn 370 375 380 Glu Trp Leu Asn Tyr Asp Ile Tyr Ile Pro Asp Leu Pro Arg Ala Ala 385 390 395 400 Arg Leu Cys Leu Ser Ile Cys Ser Val Lys Gly Arg Lys Gly Ala Lys 405 410 415 Glu Glu His Cys Pro Leu Ala Tr p Gly Asn Ile Asn Leu Phe Asp Tyr 420 425 430 Thr Asp Thr Leu Val Ser Gly Lys Met Ala Leu Asn Leu Trp Pro Val 435 440 445 Pro His Gly Leu Glu Asp Leu Leu Asn Pro Ile Gly Val Thr Gly Ser 450 455 460 Asn Pro Asn Lys Glu Thr Pro Cys Leu Glu Leu Glu Phe Asp Trp Phe 465 470 475 480 Ser Ser Val Val Lys Phe Pro Asp Met Ser Val Ile Glu Glu His Ala 485 490 495 Asn Trp Ser Val Ser Arg Glu Ala Gly Phe Ser Tyr Ser His Ala Gly 500 505 510 Leu Ser Asn Arg Leu Ala Arg Asp Asn Glu Leu Arg Glu Asn Asp Lys 515 520 525 Glu Gln Leu Lys Ala Ile Ser Thr Arg Asp Pro Leu Ser Glu Ile Thr 530 535 540 Glu Gln Glu Lys Asp Phe Leu Trp Ser His Arg His Tyr Cys Val Thr 545 550 555 560 Ile Pro Glu Ile Leu Pro Lys Leu Leu Leu Ser Val Lys Trp Asn Ser 565 570 575 Arg Asp Glu Val Ala Gln Met Tyr Cys Leu Val Lys Asp Trp Pro Pro 580 585 590 Ile Lys Pro Glu Gln Ala Met Glu Leu Leu Asp Cys Asn Tyr Pro Asp 595 600 605 Pro Met Val Arg Gly Phe Ala Val Arg Cys Leu Glu Lys Tyr Leu Thr 610 615 620 Asp Asp Lys Leu Ser Gln Tyr Leu Ile Gln Leu Val Gln Val Leu Lys 625 630 635 640 Tyr Glu Gln Tyr Leu Asp Asn Leu Leu Val Arg Phe Leu Leu Lys Lys 645 650 655 Ala Leu Thr Asn Gln Arg Ile Gly His Phe Phe Phe Trp His Leu Lys 660 665 670 Ser Glu Met His Asn Lys Thr Val Ser Gln Arg Phe Gly Leu Leu Leu Leu 675 680 685 Glu Ser Tyr Cys Arg Ala Cys Gly Met Tyr Leu Lys His Leu Asn Arg 690 695 700 Gln Val Glu Ala Met Glu Lys Leu Ile Asn Leu Thr Asp Ile Leu Lys 705 710 715 720 Gln Glu Lys Lys Asp Glu Thr Gln Lys Val Gln Met Lys Phe Leu Val 725 730 735 Glu Gln Met Arg Arg Pro Asp Phe Met Asp Ala Leu Gln Gly Phe Leu 740 745 750 Ser Pro Leu Asn Pro Ala His Gln Leu Gly Asn Leu Arg Leu Glu Glu 755 760 765 Cys Arg Ile Met Ser Ser Ala Lys Arg Pro Leu Trp Leu Asn Trp Glu 770 775 780 Asn Pro Asp Ile Met Ser Glu Leu Leu Phe Gln Asn Asn Glu Ile Ile 785 790 795 800 Phe Lys Asn Gly Asp Asp Leu Arg Gln Asp Met Leu Thr Leu Gln Ile 805 810 815 Ile Arg Ile Met Glu Asn Ile Trp Gln Asn Gln Gly Leu Asp Leu Arg 820 825 830 Met Leu Pro Tyr Gly Cys Leu Ser Ile Gly Asp Cys Val Gly Leu Ile 835 840 845 Glu Val Val Arg Asn Ser His Thr Ile Met Gln Ile Gln Cys Lys Gly 850 855 860 Gly Leu Lys Gly Ala Leu Gln Phe Asn Ser His Thr Leu His Gln Trp 865 870 875 880 Leu Lys Asp Lys Asn Lys Gly Glu Ile Tyr Asp Ala Ala Ile Asp Leu 885 890 895 Phe Thr Arg Ser Cys Ala Gly Tyr Cys Val Ala Thr Phe Ile Leu Gly 900 905 910 Ile Gly Asp Arg His Asn Ser Asn Ile Met Val Lys Asp Asp Gly Gln 915 920 925 Leu Phe His Ile Asp Phe Gly His Phe Leu Asp His Lys Lys Lys Lys 930 935 940 Phe Gly Tyr Lys Arg Glu Arg Val Pro Phe Val Leu Thr Gln Asp Phe 945 950 955 960 Leu Ile Val Ile Ser Lys Gly Ala Gln Glu Cys Thr Lys Thr Arg Glu 965 970 975 Phe Glu Arg Phe Gln Glu Met Cys Tyr Lys Ala Tyr Leu Ala Ile Arg 980 985 990 Gln His Ala Asn Leu Phe Ile Asn Leu Phe Ser Met Met Leu Gly Ser 995 1000 1005 Gly Met Pro Glu Leu Gln Ser Phe Asp Asp Ile Ala Tyr Ile Arg Lys 1010 1015 1020 Thr Leu Ala Leu Asp Lys Thr Glu Gln Glu Ala Leu Glu Tyr Phe Met 1025 1030 1035 1040 Lys Gln Met Asn Asp Ala His Gly Gly Trp Thr Thr Lys Met Asp 1045 1050 1055 Trp Ile Phe His Thr Ile Lys Gln His Ala Leu Asn 1060 1065 <210> 11 <211> 1052 <212> PRT <213> Homo sapiens <400> 11 Met Ala Ala Ala Tyr Leu Asp Pro Asn Leu Asn His Thr Pro Asn Ser 1 5 10 15 Ser Thr Lys Thr His Leu Gly Thr Gly Met Glu Arg Ser Pro Gly Ala 20 25 30 Met Glu Arg Val Leu Lys Val Phe His Tyr Phe Glu Ser Asn Ser Glu 35 40 45 Pro Thr Thr Trp Ala Ser Ile Ile Arg His Gly Asp Ala Thr Asp Val 50 55 60 Arg Gly Ile Ile Gln Lys Ile Val Asp Ser His Lys Val Lys His Val 65 70 75 80 Ala Cys Tyr Gly Phe Arg Leu Ser His Leu Arg Ser Glu Glu Val His 85 90 95 Trp Leu His Val Asp Met Gly Val Ser Ser Val Arg Glu Lys Tyr Glu 100 105 110 Leu Ala His Pro Pro Glu Glu Trp Lys Tyr Glu Leu Arg Ile Arg Tyr 115 120 125 Leu Pro Lys Gly Phe Leu Asn Gln Phe Thr Glu Asp Lys Pro Thr Leu 130 135 140 Asn Phe Phe Tyr Gln Gln Val Lys Ser Asp Tyr Met Leu Glu Ile Ala 145 150 155 160 Asp Gln Val Asp Gln Glu Ile Ala Leu Lys Leu Gly Cys Leu Glu Ile 165 170 175 Arg Arg Ser Tyr Trp Glu Met Arg Gly Asn Ala Leu Glu Lys Lys Ser 180 185 190 Asn Tyr Glu Val Leu Glu Lys Asp Val Gly Leu Lys Arg Phe Phe Pro 195 200 205 Lys Ser Leu Leu Asp Ser Val Lys Ala Lys Thr Leu Arg Lys Leu Ile 210 215 220 Gln Gln Thr Phe Arg Gln Phe Ala Asn Leu Asn Arg Glu Glu Ser Ile 225 230 235 240 Leu Lys Phe Phe Glu Ile Leu Ser Pro Val Tyr Arg Phe Asp Lys Glu 245 250 255 Cys Phe Lys Cys Ala Leu Gly Ser Ser Trp Ile Ile Ser Val Glu Leu 260 265 270 Ala Ile Gly Pro Glu Glu Gly Ile Ser Tyr Leu Thr Asp Lys Gly Cys 275 280 285 Asn Pro Thr His Leu Ala Asp Phe Thr Gln Val Gln Thr Ile Gln Tyr 290 295 300 Ser Asn Ser Glu Asp Lys Asp Arg Lys Gly Met Leu Gln Leu Lys Ile 305 310 315 320 Ala Gly Ala Pro Glu Pro Leu Thr Val Thr Ala Pro Ser Leu Thr Ile 325 330 335 Ala Glu Asn Met Ala Asp Leu Ile Asp Gly Tyr Cys Arg Leu Val Asn 340 345 350 Gly Thr Ser Gln Ser Phe Ile Ile Arg Pro Gln Lys Glu Gly Glu Arg 355 360 365 Ala Leu Pro Ser Ile Pro Lys Leu Ala Asn Ser Glu Lys Gln Gly Met 370 375 380 Arg Thr His Ala Val Ser Val Ser Glu Thr Asp Asp Tyr Ala Glu Ile 385 390 395 400 Ile Asp Glu Glu Asp Thr Tyr Thr Met Pro Ser Thr Arg Asp Tyr Glu 405 410 415 Ile Gln Arg Glu Arg Ile Glu Leu Gly Arg Cys Ile Gly Glu Gly Gln 420 425 430 Phe Gly Asp Val His Gin Gly Ile Tyr Met Ser Pro Glu Asn Pro Ala 435 440 445 Leu Ala Val Ala Ile Lys Thr Cys Lys Asn Cys Thr Ser Asp Ser Val 450 455 460 Arg Glu Lys Phe Leu Gln Glu Ala Leu Thr Met Arg Gln Phe Asp His 465 470 475 480 Pro His Ile Val Lys Leu Ile Gly Val Ile Thr Glu Asn Pro Val Trp 485 490 495 Ile Ile Met Glu Leu Cys Thr Leu Gly Glu Leu Arg Ser Phe Leu Gln 500 505 510 Val Arg Lys Tyr Ser Leu Asp Leu Ala Ser Leu Ile Leu Tyr Ala Tyr 515 520 525 Gln Leu Ser Thr Ala Leu Ala Tyr Leu Glu Ser Lys Arg Phe Val His 530 535 540 Arg Asp Ile Ala Ala Arg Asn Val Leu Val Ser Ser Asn Asp Cys Val 545 550 555 560 Lys Leu Gly Asp Phe Gly Leu Ser Arg Tyr Met Glu Asp Ser Thr Tyr 565 570 575 Tyr Lys Ala Ser Lys Gly Lys Leu Pro Ile Lys Trp Met Ala Pro Glu 580 585 590 Ser Ile Asn Phe Arg Arg Phe Thr Ser Ala Ser Asp Val Trp Met Phe 595 600 605 Gly Val Cys Met Trp Glu Ile Leu Met His Gly Val Lys Pro Phe Gln 610 615 620 Gly Val Lys Asn Asn Asp Val Ile Gly Arg Ile Glu Asn Gly Glu Arg 625 630 635 640 Leu Pro Met Pro Pro Asn Cys Pro Pro Thr Leu Tyr Ser Leu Met Thr 645 650 655 Lys Cys Trp Ala Tyr Asp Pro Ser Arg Arg Pro Arg Phe Thr Glu Leu 660 665 670 Lys Ala Gln Leu Ser Thr Ile Leu Glu Glu Glu Lys Ala Gln Gln Glu 675 680 685 Glu Arg Met Arg Met Glu Ser Arg Arg Gln Ala Thr Val Ser Trp Asp 690 695 700 Ser Gly Gly Ser Asp Glu Ala Pro Pro Lys Pro Ser Arg Pro Gly Tyr 705 710 715 720 Pro Ser Pro Arg Ser Ser Glu Gly Phe Tyr Pro Ser Pro Gln His Met 725 730 735 Val Gln Thr Asn His Tyr Gln Val Ser Gly Tyr Pro Gly Ser His Gly 740 745 750 Ile Thr Ala Met Ala Gly Ser Ile Tyr Pro Gly Gln Ala Ser Leu Leu 755 760 765 Asp Gln Thr Asp Ser Trp Asn His Arg Pro Gln Glu Ile Ala Met Trp 770 775 780 Gln Pro Asn Val Glu Asp Ser Thr Val Leu Asp Leu Arg Gly Ile Gly 785 790 795 800 Gln Val Leu Pro Thr His Leu Met Glu Glu Arg Leu Ile Arg Gln Gln 805 810 815 Gln Glu Met Glu Glu Asp Gln Arg Trp Leu Glu Lys Glu Glu Arg Phe 820 825 830 Leu Lys Pro Asp Val Arg Leu Ser Arg Gly Ser Ile Asp Arg Glu Asp 835 840 845 Gly Ser Leu Gln Gly Pro Ile Gly Asn Gln His Ile Tyr Gln Pro Val 850 855 860 Gly Lys Pro Asp Pro Ala Ala Pro Pro Lys Lys Pro Pro Arg Pro Gly 865 870 875 880 Ala Pro Gly His Leu Gly Ser Leu Ala Ser Leu Ser Ser Pro Ala Asp 885 890 895 Ser Tyr Asn Glu Gly Val Lys Leu Gln Pro Gln Glu Ile Ser Pro 900 905 910 Pro Thr Ala Asn Leu Asp Arg Ser Asn Asp Lys Val Tyr Glu Asn Val 915 920 925 Thr Gly Leu Val Lys Ala Val Ile Glu Met Ser Ser Lys Ile Gln Pro 930 935 940 Ala Pro Pro Glu Glu Tyr Val Pro Met Val Lys Glu Val Gly Leu Ala 945 950 955 960 Leu Arg Thr Leu Leu Ala Thr Val Asp Glu Thr Ile Pro Leu Leu Pro 965 970 975 Ala Ser Thr His Arg Glu Ile Glu Met Ala Gln Lys Leu Leu Asn Ser 980 985 990 Asp Leu Gly Glu Leu Ile Asn Lys Met Lys Leu Ala Gln Gln Tyr Val 995 1000 1005 Met Thr Ser Leu Gln Gln Glu Tyr Lys Lys Gln Met Leu Thr Al a Ala 1010 1015 1020 His Ala Leu Ala Val Asp Ala Lys Asn Leu Leu Asp Val Ile Asp Gln 1025 1030 1035 1040 Ala Arg Leu Lys Met Leu Gly Gln Thr Arg Pro His 1045 1050 <210> 12 <211> 928 <212> PRT <213> Homo sapiens <400> 12 Met Pro Pro Lys Thr Pro Arg Lys Thr Ala Ala Thr Ala Ala Ala Ala 1 5 10 15 Ala Ala Glu Pro Pro Ala Pro Pro Pro Pro Pro Pro Glu Glu Asp 20 25 30 Pro Glu Gln Asp Ser Gly Pro Glu Asp Leu Pro Leu Val Arg Leu Glu 35 40 45 Phe Glu Glu Thr Glu Glu Pro Asp Phe Thr Ala Leu Cys Gln Lys Leu 50 55 60 Lys Ile Pro Asp His Val Arg Glu Arg Ala Trp Leu Thr Trp Glu Lys 65 70 75 80 Val Ser Ser Val Asp Gly Val Leu Gly Gly Tyr Ile Gln Lys Lys Lys 85 90 95 Glu Leu Trp Gly Ile Cys Ile Phe Ile Ala Ala Val Asp Leu Asp Glu 100 105 110 Met Ser Phe Thr Phe Thr Glu Leu Gln Lys Asn Ile Glu Ile Ser Val 115 120 125 His Lys Phe Phe Asn Leu Leu Lys Glu Ile Asp Thr Ser Thr Lys Val 130 135 140 Asp Asn Ala Met Ser Arg Leu Leu Lys Lys Tyr Asp Val Leu Phe Ala 145 150 155 160 Leu Phe Ser Lys Leu Glu Arg Thr Cys Glu Leu Ile Tyr Leu Thr Gln 165 170 175 Pro Ser Ser Ser Ile Ser Thr Glu Ile Asn Ser Ala Leu Val Leu Lys 180 185 190 Val Ser Trp Ile Thr Phe Leu Leu Ala Lys Gly Glu Val Leu Gln Met 195 200 205 Glu Asp Asp Leu Val Ile Ser Phe Gln Leu Met Leu Cys Val Leu Asp 210 215 220 Tyr Phe Ile Lys Leu Ser Pro Pro Met Leu Leu Lys Glu Pro Tyr Lys 225 230 235 240 Thr Ala Val Ile Pro Ile Asn Gly Ser Pro Arg Thr Pro Arg Arg Gly 245 250 255 Gln Asn Arg Ser Ala Arg Ile Ala Lys Gln Leu Glu Asn Asp Thr Arg 260 265 270 Ile Ile Glu Val Leu Cys Lys Glu His Glu Cys Asn Ile Asp Glu Val 275 280 285 Lys Asn Val Tyr Phe Lys Asn Phe Ile Pro Phe Met Asn Ser Leu Gly 290 295 300 Leu Val Thr Ser Asn Gly Leu Pro Glu Val Glu Asn Leu Ser Lys Arg 305 310 315 320 Tyr Glu Glu Ile Tyr Leu Lys Asn Lys Asp Leu Asp Ala Arg Leu Phe 325 330 335 Leu Asp His Asp Lys Thr Leu Gln Thr Asp Ser Ile Asp Ser Phe Glu 340 345 350 Thr Gln Arg Thr Pro Arg Lys Ser Asn Leu Asp Glu Glu Val Asn Val 355 360 365 Ile Pro Pro His Thr Pro Val Arg Thr Val Met Asn Thr Ile Gln Gln 370 375 380 Leu Met Met Ile Leu Asn Ser Ala Ser Asp Gln Pro Ser Glu Asn Leu 385 390 395 400 Ile Ser Tyr Phe Asn Asn Cys Thr Val Asn Pro Lys Glu Ser Ile Leu 405 410 415 Lys Arg Val Lys Asp Ile Gly Tyr Ile Phe Lys Glu Lys Phe Ala Lys 420 425 430 Ala Val Gly Gln Gly Cys Val Glu Ile Gly Ser Gln Arg Tyr Lys Leu 435 440 445 Gly Val Arg Leu Tyr Tyr Arg Val Met Glu Ser Met Leu Lys Ser Glu 450 455 460 Glu Glu Arg Leu Ser Ile Gln Asn Phe Ser Lys Leu Leu Asn Asp Asn 465 470 475 480 Ile Phe His Met Ser Leu Leu Ala Cys Ala Leu Glu Val Val Met Ala 485 490 495 Thr Tyr Ser Arg Ser Thr Ser Gln Asn Leu Asp Ser Gly Thr Asp Leu 500 505 510 Ser Phe Pro Trp Ile Leu Asn Val Leu Asn Leu Lys Ala Phe Asp Phe 515 520 525 Tyr Lys Val Ile Glu Ser Phe Ile Lys Ala Glu Gly Asn Leu Thr Arg 530 535 540 Glu Met Ile Lys His Leu Glu Arg Cys Glu His Arg Ile Met Glu Ser 545 550 555 560 Leu Ala Trp Leu Ser Asp Ser Pro Leu Phe Asp Leu Ile Lys Gln Ser 565 570 575 Lys Asp Arg Glu Gly Pro Thr Asp His Leu Glu Ser Ala Cys Pro Leu 580 585 590 Asn Leu Pro Leu Gln Asn Asn His Thr Ala Ala Asp Met Tyr Leu Ser 595 600 605 Pro Val Arg Ser Pro Lys Lys Lys Gly Ser Thr Thr Arg Val Asn Ser 610 615 620 Thr Ala Asn Ala Glu Thr Gln Ala Thr Ser Ala Phe Gln Thr Gln Lys 625 630 635 640 Pro Leu Lys Ser Thr Ser Leu Ser Leu Phe Tyr Lys Lys Val Tyr Arg 645 650 655 Leu Ala Tyr Leu Arg Leu Asn Thr Leu Cys Glu Arg Leu Leu Ser Glu 660 665 670 His Pro Glu Leu Glu His Ile Ile Trp Thr Leu Phe Gln His Thr Leu 675 680 685 Gln Asn Glu Tyr Glu Leu Met Arg Asp Arg His Leu Asp Gln Ile Met 690 695 700 Met Cys Ser Met Tyr Gly Ile Cys Lys Val Lys Asn Ile Asp Leu Lys 705 710 715 720 Phe Lys Ile Ile Val Thr Ala Tyr Lys Asp Leu Pro His Ala Val Gln 725 730 735 Glu Thr Phe Lys Arg Val Leu Ile Lys Glu Glu Glu Tyr Asp Ser Ile 740 745 750 Ile Val Phe Tyr Asn Ser Val Phe Met Gln Arg Leu Lys Thr Asn Ile 755 760 765 Leu Gln Tyr Ala Ser Thr Arg Pro Pro Thr Leu Ser Pro Ile Pro His 770 775 780 Ile Pro Arg Ser Pro Tyr Lys Phe Pro Ser Ser Pro Leu Arg Ile Pro 785 790 795 800 Gly Gly Asn Ile Tyr Ile Ser Pro Leu Lys Ser Pro Tyr Lys Ile Ser 805 810 815 Glu Gly Leu Pro Thr Pro Thr Lys Met Thr Pro Arg Ser Arg Ile Leu 820 825 830 Val Ser Ile Gly Glu Ser Phe Gly Thr Ser Glu Lys Phe Gln Lys Ile 835 840 845 Asn Gln Met Val Cys Asn Ser Asp Arg Val Leu Lys Arg Ser Ala Glu 850 855 860 Gly Ser Asn Pro Pro Lys Pro Leu Lys Lys Leu Arg Phe Asp Ile Glu 865 870 875 880 Gly Ser Asp Glu Ala Asp Gly Ser Lys His Leu Pro Gly Glu Ser Lys 885 890 895 Phe Gln Gln Lys Leu Ala Glu Met Thr Ser Thr Arg Thr Arg Met Gln 900 905 910Lys Gln Lys Met Asn Asp Ser Met Asp Thr Ser Asn Lys Glu Glu Lys 915 920 925
Claims (20)
상기 아형으로 분류하는 단계 시 목적하는 개체로부터 분리된 생물학적 시료에서 SPOP, PRDM1, ETS, PTEN, TP53, PIK3CA, PTK2 및 RB1 유전자로 이루어진 군에서 선택된 적어도 하나의 유전자의 돌연변이 여부를 검출하여 수행되는 것인, 방법.According to claim 1,
In the step of classifying into the subtype, at least one gene selected from the group consisting of SPOP, PRDM1, ETS, PTEN, TP53, PIK3CA, PTK2 and RB1 genes in a biological sample isolated from a target individual is mutated by detecting whether or not it is performed. In, way.
상기 돌연변이는 결실(deletion), 중복(duplication), 역위(inversion), 전좌(translocation), 염기치환(base substitution), 삽입(insertion) 및 융합(fusion)에서 선택된 하나 이상인 것인, 방법.3. The method of claim 2,
The mutation is one or more selected from deletion (deletion), duplication (duplication), inversion (inversion), translocation (translocation), base substitution (base substitution), insertion (insertion) and fusion (fusion).
상기 루미널 A 아형은 SPOP 돌연변이 및 PRDM1 결실 중 적어도 하나를 포함하는 것인, 방법. 4. The method of claim 3,
The method of claim 1, wherein the luminal A subtype comprises at least one of a SPOP mutation and a PRDM1 deletion.
상기 루미널 S 아형은 ETS 융합 및 PTEN 결실을 포함하고, TP53 돌연변이를 포함하지 않는 것인, 방법.4. The method of claim 3,
wherein the luminal S subtype comprises an ETS fusion and a PTEN deletion and does not comprise a TP53 mutation.
상기 AVPC-I 아형은 TP53 돌연변이를 포함하고, PIK3CA 돌연변이를 포함하지 않는 것인, 방법.4. The method of claim 3,
The method of claim 1, wherein the AVPC-I subtype includes a TP53 mutation and does not include a PIK3CA mutation.
상기 AVPC-M 아형은 PIK3CA 돌연변이를 포함하는 것인, 방법.4. The method of claim 3,
The method of claim 1, wherein the AVPC-M subtype comprises a PIK3CA mutation.
상기 유전자의 돌연변이 여부를 검출하거나 상기 유전자의 발현 정도를 확인하는 분석 방법으로는 역전사 중합효소반응(RT-PCR), 경쟁적 역전사 중합효소반응(Competitive RT-PCR), 실시간 역전사 중합효소반응(Real-time RT-PCR), RNase 보호 분석법(RPA; RNase protection assay), 노던 블랏팅(Northern blotting), DNA 칩 및 RNA 시퀸싱으로 이루어진 군에서 선택된 1종 이상을 포함하는 것인, 방법.4. The method of claim 3,
As an analysis method for detecting whether the gene is mutated or confirming the expression level of the gene, reverse transcription polymerase reaction (RT-PCR), competitive reverse transcription polymerase reaction (Competitive RT-PCR), real-time reverse transcription polymerase reaction (Real- time RT-PCR), RNase protection assay (RPA; RNase protection assay), Northern blotting (Northern blotting), the method comprising at least one selected from the group consisting of DNA chip and RNA sequencing.
상기 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형 중 어느 2개의 아형은 KLK3, ACP3, ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B, PCA3, CDC20, MYBL2, COL10A1, ALOX15, ANKRD34B, KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B, TRPM8, HDAC9, ETV1, BEX1, ATP1A1, ERG, APOD, TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1, ALOX15B, ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B, COL2A1, NIPAL3, TSPAN19, RFPL1S, CPM, NEFH, CEACAM5, YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 및 CHGA로 이루어진 군에서 선택된 1종 이상의 유전자의 발현 패턴이 상이한, 방법.The method of claim 1,
Any two subtypes of the luminal A subtype, the luminal S subtype, the AVPC-I subtype and the AVPC-M subtype are KLK3, ACP3, ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B, PCA3, CDC20, MYBL2, COL10A1, ALOX15, ANKRD34B, KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B, TRPM8, HDAC9, ETV1, BEX1, ATP1A1, ERG, APOD, TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1, ALOX15, ANKERG8 The expression pattern of one or more genes selected from the group consisting of LINC02418, ALOX15, ANKRD34B, COL2A1, NIPAL3, TSPAN19, RFPL1S, CPM, NEFH, CEACAM5, YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 and CHGA is different Way.
상기 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형 각각은 목적하는 개체로부터 분리된 생물학적 시료 내 PAP 단백질의 발현 수준에 대한 PSA 단백질의 발현 수준의 비율(PSA/PAP)이 서로 동일하거나 상이한 것인, 방법.According to claim 1,
Each of the luminal A subtype, luminal S subtype, AVPC-I subtype and AVPC-M subtype is the ratio of the expression level of the PSA protein to the expression level of the PAP protein in the biological sample isolated from the subject of interest (PSA/PAP) are the same or different from each other.
상기 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형은 각각 항암제에 대하여 상이한 감수성을 보이는 것인, 방법.According to claim 1,
The luminal A subtype, the luminal S subtype, the AVPC-I subtype and the AVPC-M subtype each show a different sensitivity to an anticancer agent, the method.
상기 항암제는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 소라페닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 데시타빈, 카페시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 아나스트로졸, 레트로졸, 보로졸, 로무스틴, 보리노스텟, 엔티노스텟, 카르무스틴, 안드로겐 억제제 및 도세탁셀에서 선택된 어느 하나 이상인 것인, 방법.12. The method of claim 11,
The anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib, resta Urtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, viscumalbum, asparaginase, tretinoin, hydroxycarbamide, Dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tusetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, Gemcitabine, doxyfluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, fluorouracil, fludagabine, enocitabine, Decitabine, capecitabine, mercaptopurine, thioguanine, cladribine, carmopher, raltitrexed, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide , doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide , busulfan, ifosfamide, cyclophosphamide, melparan, altretmine, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exemestane, aminoglute From simid, anagrelide, nabelbine, fadrazole, tamoxifen, toremifene, anastrozole, letrozole, vorozole, lomustine, vorinostat, entinostat, carmustine, androgen inhibitors and docetaxel Any one or more selected, the method.
상기 연산부는 목적하는 개체로부터 분리된 생물학적 시료에서 SPOP, PRDM1, ETS, PTEN, TP53, PIK3CA 및 PTK2 유전자에서 선택된 적어도 하나의 유전자의 돌연변이 여부를 검출하는 검출부를 더 포함하는 것인, 장치.14. The method of claim 13,
The operation unit further comprises a detection unit for detecting whether at least one gene selected from SPOP, PRDM1, ETS, PTEN, TP53, PIK3CA and PTK2 genes in a biological sample isolated from a target individual is mutated.
상기 돌연변이는 결실(deletion), 중복(duplication), 역위(inversion), 전좌(translocation), 염기치환(base substitution), 삽입(insertion) 및 융합(fusion)에서 선택된 하나 이상인 것인, 장치.15. The method of claim 14,
The mutation is one or more selected from deletion, duplication, inversion, translocation, base substitution, insertion and fusion, the device.
상기 루미널 A 아형은 SPOP 돌연변이 및 PRDM1 결실 중 적어도 하나를 포함하는 것이고,
상기 루미널 S 아형은 ETS 융합 및 PTEN 결실을 포함하고, TP53 돌연변이를 포함하지 않는 것이며,
상기 AVPC-I 아형은 TP53 돌연변이를 포함하고, PIK3CA 돌연변이를 포함하지 않는 것이고,
상기 AVPC-M 아형은 PIK3CA 돌연변이를 포함하는 것인, 장치.15. The method of claim 14,
wherein the luminal A subtype comprises at least one of a SPOP mutation and a PRDM1 deletion,
wherein the luminal S subtype contains an ETS fusion and a PTEN deletion, and does not contain a TP53 mutation;
wherein the AVPC-I subtype includes a TP53 mutation and does not include a PIK3CA mutation,
The device of claim 1, wherein the AVPC-M subtype comprises a PIK3CA mutation.
상기 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형 중 어느 2개의 아형은 KLK3, ACP3, ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B, PCA3, CDC20, MYBL2, COL10A1, ALOX15, ANKRD34B, KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B, TRPM8, HDAC9, ETV1, BEX1, ATP1A1, ERG, APOD, TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1, ALOX15B, ANKRD6, PDE8B, ERG, LINC02418, ALOX15, ANKRD34B, COL2A1, NIPAL3, TSPAN19, RFPL1S, CPM, NEFH, CEACAM5, YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 및 CHGA로 이루어진 군에서 선택된 1종 이상의 유전자의 발현 패턴이 상이한, 장치.14. The method of claim 13,
Any two subtypes of the luminal A subtype, the luminal S subtype, the AVPC-I subtype and the AVPC-M subtype are KLK3, ACP3, ANPEP, RLN1, PCAT4, PCGEM1, ALOX15B, PCA3, CDC20, MYBL2, COL10A1, ALOX15, ANKRD34B, KLK2, MESP1, KLK4, SLC45A3, ABCC4, FAM3B, TRPM8, HDAC9, ETV1, BEX1, ATP1A1, ERG, APOD, TFF3, MESP1, MESP2, GNG13, FABP5, UNC5A, SPINK1, ALOX15, ANKERG8 The expression pattern of one or more genes selected from the group consisting of LINC02418, ALOX15, ANKRD34B, COL2A1, NIPAL3, TSPAN19, RFPL1S, CPM, NEFH, CEACAM5, YPEL1, SULT4A1, MMEL1, TDRD1, CRISP3, NKX2-1 and CHGA is different Device.
상기 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형은 목적하는 개체로부터 분리된 생물학적 시료 내 PAP 단백질의 발현 수준에 대한 PSA 단백질의 발현 수준의 비율(PSA/PAP)이 서로 동일하거나 상이한 것인, 장치.14. The method of claim 13,
The luminal A subtype, luminal S subtype, AVPC-I subtype and AVPC-M subtype have a ratio of the expression level of the PSA protein to the expression level of the PAP protein in the biological sample isolated from the subject of interest (PSA/PAP). the same or different from each other.
상기 루미널 A 아형, 루미널 S 아형, AVPC-I 아형 및 AVPC-M 아형은 각각 항암제에 대하여 상이한 감수성을 보이는 것인, 장치.14. The method of claim 13,
The luminal A subtype, luminal S subtype, AVPC-I subtype and AVPC-M subtype will each show a different sensitivity to an anticancer agent, the device.
상기 항암제는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 소라페닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 데시타빈, 카페시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 아나스트로졸, 레트로졸, 보로졸, 로무스틴, 보리노스텟, 엔티노스텟, 카르무스틴, 안드로겐 억제제 및 도세탁셀에서 선택된 어느 하나 이상인 것인, 장치.20. The method of claim 19,
The anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib, resta Urtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, viscumalbum, asparaginase, tretinoin, hydroxycarbamide, Dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tusetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, Gemcitabine, doxyfluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, fluorouracil, fludagabine, enocitabine, Decitabine, capecitabine, mercaptopurine, thioguanine, cladribine, carmopher, raltitrexed, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide , doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide , busulfan, ifosfamide, cyclophosphamide, melparan, altretmine, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exemestane, aminoglute From simid, anagrelide, nabelbine, fadrazole, tamoxifen, toremifene, anastrozole, letrozole, vorozole, lomustine, vorinostat, entinostat, carmustine, androgen inhibitors and docetaxel Any one or more selected, the device.
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