KR20210049684A - Composition for Classification of Encapsulated Follicular variant of Papillary Thyroid Carcinoma(EFVPTC) with Non-invasive follicular thyroid neoplasm with papillary-like nuclear features(NIFTP) and Classification Method Using the Same - Google Patents

Composition for Classification of Encapsulated Follicular variant of Papillary Thyroid Carcinoma(EFVPTC) with Non-invasive follicular thyroid neoplasm with papillary-like nuclear features(NIFTP) and Classification Method Using the Same Download PDF

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KR20210049684A
KR20210049684A KR1020200137014A KR20200137014A KR20210049684A KR 20210049684 A KR20210049684 A KR 20210049684A KR 1020200137014 A KR1020200137014 A KR 1020200137014A KR 20200137014 A KR20200137014 A KR 20200137014A KR 20210049684 A KR20210049684 A KR 20210049684A
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Abstract

The present invention relates to a composition for classifying an infiltrative encapsulated follicular variant of papillary thyroid carcinoma and papillary carcinoma-like nuclear non-invasive follicular tumor, a classification method using the same, a classification kit, and the like.

Description

피막형 여포변이 갑상선 유두암과 유두암종유사핵모양비침습소포종양 분류용 조성물 및 이를 이용한 분류 방법{Composition for Classification of Encapsulated Follicular variant of Papillary Thyroid Carcinoma(EFVPTC) with Non-invasive follicular thyroid neoplasm with papillary-like nuclear features(NIFTP) and Classification Method Using the Same}Composition for Classification of Encapsulated Follicular variant of Papillary Thyroid Carcinoma(EFVPTC) with Non-invasive follicular thyroid neoplasm with papillary-like nuclear features(NIFTP) and Classification Method Using the Same}

본 발명은 피막형 여포 변이 갑상선 유두암과 유두암종유사핵모양비침습소포종양의 분류용 조성물 및 이를 이용한 분류 방법, 및 분류 키트 등에 관한 것이다.The present invention relates to a composition for classification of capsular follicular mutant thyroid papillary cancer and papillary cancer tumor-like nucleated non-invasive vesicle tumors, a classification method using the same, and a classification kit.

갑상선 유두암(papillary thyroid carcinoma, PTC)은 10개 내외의 변종 혹은 아종을 가지고 있으며 가장 흔한 변종은 여포성 변종(follicular variant papillary thyroid carcinoma, FVPTC)으로 전체 갑상선 유두암의 약 10-20%를 차지한다. FVPTC는 다시 피막을 가지고 있는 FVPTC(Encapsulated FVPTC, EFVPTC)와 피막을 가지고 있지 않은 것 Infiltrative FVPTC로 분류가능하며 EFVPTC도 피막침윤, 혈관 침윤 등의 소견을 보이는 침윤성(invasive EFVPTC)과 비침윤성(non invasive EFVPTC)으로 다시 분류할 수 있다. 피막이 있는 경우 영상학적으로는 isoechoic한 균질성의 종양으로 주위에 hollow를 보이는 여포성종양의 소견을 보이는 경우가 많다. 병리학적으로 FVPTC는 일반적인 PTC의 핵의 모양을 가지고 있으면서 micro-follicular formation을 하고 있는, 즉 여포성종양과 유사한 cyto-pathologic architecture를 가지고 있는 종양으로 정의할 수 있는데 infiltrative PTC의 경우 일반적인 PTC와 동일한 예후를 보이는 반면 non invasive EFVPTC의 경우 굉장히 좋은 예후를 보인다는 사실은 잘 알려져 있다. Papillary thyroid carcinoma (PTC) has about 10 variants or subspecies, and the most common variant is follicular variant papillary thyroid carcinoma (FVPTC), which accounts for about 10-20% of all thyroid papillary cancer. FVPTC can be classified as infiltrative FVPTC (Encapsulated FVPTC, EFVPTC) with a film and infiltrative FVPTC. EFVPTC) can be classified again. In the case of the encapsulation, it is an isoechoic homogeneous tumor in many cases, showing a hollow follicular tumor around the periphery. Pathologically, FVPTC can be defined as a tumor that has micro-follicular formation while having a nuclear shape of a general PTC, that is, a tumor that has a cyto-pathologic architecture similar to a follicular tumor. In the case of infiltrative PTC, the prognosis is the same as that of a general PTC. On the other hand, it is well known that non-invasive EFVPTC has a very good prognosis.

최근 미국 피츠버그 대학의 Yuri Nikiforov 교수 팀에서 non invasive EFVPTC의 경우 109명의 환자 중 수술 후 추적기간(10-26년, median 13년) 중 재발이나 사망이 한 건도 없었다고 보고하면서 non invasive EFVPTC를 Non Invasive Follicular Thyroid neoplasm with Papillary-like nuclear feature (NIFTP)로 개명하고 암 분류에서 제외하고 양성종양으로 분류하자는 주장을 하였고, 병리적인 진단 지침을 새롭게 제시하였다. 최근에 개정된 국제보건기구 (World Health Organization, WHO) 내분비종양 분류 책에서는 NIFTP가 악성 종양이 아닌 갑상선 경계성 종양으로 분류되기 시작했다. Recently, Professor Yuri Nikiforov's team at the University of Pittsburgh reported that there was no recurrence or death during the postoperative follow-up period (10-26 years, median 13 years) among 109 patients with non-invasive EFVPTC. Renamed Thyroid neoplasm with Papillary-like nuclear feature (NIFTP) and claimed to be excluded from cancer classification and classified as benign tumors, and a new guideline for pathologic diagnosis was proposed. In the recently revised World Health Organization (WHO) Endocrine Tumor Classification, NIFTP began to be classified as a borderline thyroid tumor, not a malignant tumor.

NIFTP는 현재의 기술로는 수술 후 병리 검사에서 종양 전체를 정밀검사하고 때로는 면역조직화학까지 동반해야 진단할 수 있는 개념으로 진단하기 위해서는 수술에 의한 종양 적출이 전제 되어 있는 개념이다. 즉 불필요한 수술을 줄이기 위해서는 갑상선 결절 조직검사의 대종을 이루는 세침세포흡인검사나 중심부 생검에서 NIFTP를 진단할 수 있어야 되는데 대부분의 연구에서 최종적으로 NIFTP로 진단된 결절의 수술 전 진단은 반드시 수술이 필요하다고 인정되는 Bethesda 분류 IV 이상으로 진단되었고 일반적인 유두암을 의심하는 진단이 18%-27%나 되었다. With the current technology, NIFTP is a concept that can be diagnosed only after a detailed examination of the entire tumor in postoperative pathology and sometimes even immunohistochemistry. In order to diagnose, it is a concept that requires tumor extraction by surgery. In other words, in order to reduce unnecessary surgery, it is necessary to diagnose NIFTP by fine needle aspiration or central biopsy, which is the most common thyroid nodule biopsy.In most studies, the preoperative diagnosis of a nodule finally diagnosed with NIFTP requires surgery. It was diagnosed with a recognized Bethesda Class IV or higher, and 18%-27% of the diagnoses suspected common papillary cancer.

이와 같은 점에 비추어 볼 때, 현재까지는 결국 NIFTP를 진단하기 위해서는 수술이 필요하지만, NIFTP의 임상 진료형태를 변화시키기 위해서는 수술 전에 진단할 수 있는 방법이 확립되어야 하고, 이를 위해서는 보조적인 분자표지자 발굴 등의 노력이 필요한 실정이다.In view of these points, until now, surgery is necessary to eventually diagnose NIFTP, but in order to change the clinical treatment form of NIFTP, a diagnostic method must be established before surgery, and for this purpose, the discovery of auxiliary molecular markers, etc. It is a situation that requires effort.

Baloch ZW, Seethala RR, Faquin WC, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): A changing paradigm in thyroid surgical pathology and implications for thyroid cytopathology. Cancer Cytopathol. 2016. Baloch ZW, Seethala RR, Faquin WC, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): A changing paradigm in thyroid surgical pathology and implications for thyroid cytopathology. Cancer Cytopathol. 2016.

이에, 본 발명자들은 수술 전 NIFTP 와 침윤성 EFVPTC의 조직 시료의 단백질을 분석함으로써, NIFTP와 침윤성 EFVPTC 조직 시료 내 차별적으로 발현되는 단백질을 밝혀 본 발명을 완성하게 되었다.Accordingly, the present inventors completed the present invention by analyzing the proteins of the tissue samples of NIFTP and invasive EFVPTC before surgery, revealing proteins that are differentially expressed in the tissue samples of NIFTP and invasive EFVPTC.

따라서, 본 발명의 목적은 하기 표 11 및 표 12에 기재된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제를 유효성분으로 포함하는 침윤성 피막형 여포 변이 갑상선 유두암 (EFVPTC, Encapsulated FVPTC)과 유두암종유사핵모양비침습소포종양 (NIFTP, noninvasive follicular thyroid neoplasm with papillary- like nuclear feature)의 분류용 조성물을 제공하는 것이다.Accordingly, it is an object of the present invention to have an invasive capsular follicle mutant thyroid papillary cancer (EFVPTC, Encapsulated FVPTC) and papillary carcinoma similarity comprising as an active ingredient an agent for measuring the expression level of one or more proteins or mRNAs thereof described in Tables 11 and 12 below. To provide a composition for classification of noninvasive follicular thyroid neoplasm with papillary-like nuclear feature (NIFTP).

[표 11][Table 11]

Figure pat00001
Figure pat00001

[표 12][Table 12]

Figure pat00002
Figure pat00002

본 발명의 다른 목적은 피검체의 시료에서 상기 표 11 및 표 12에 기재된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 단계를 포함하는, 침윤성 EFVPTC와 NIFTP의 분류에 필요한 정보를 제공하는 것이다.Another object of the present invention is to provide information necessary for classification of invasive EFVPTC and NIFTP, comprising measuring the level of expression of one or more proteins or mRNAs thereof described in Tables 11 and 12 in a sample of a subject.

본 발명의 또 다른 목적은 상기 표 11 및 표 12에 기재된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제를 유효성분으로 포함하는 침윤성 EFVPTC와 NIFTP의 분류용 키트를 제공하는 것이다.Another object of the present invention is to provide a kit for classification of invasive EFVPTC and NIFTP comprising, as an active ingredient, an agent for measuring the expression level of one or more proteins or mRNAs thereof described in Tables 11 and 12.

그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems that are not mentioned will be clearly understood by those skilled in the art from the following description.

본 발명의 목적을 달성하기 위하여, 본 발명은 하기 표 11 및 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제를 유효성분으로 포함하는 침윤성 피막형 여포 변이 갑상선 유두암 (EFVPTC, Encapsulated FVPTC)과 유두암종유사핵모양비침습소포종양 (NIFTP, noninvasive follicular thyroid neoplasm with papillary-like nuclear feature)의 분류용 조성물을 제공한다.In order to achieve the object of the present invention, the present invention is an invasive capsular follicle mutant thyroid comprising as an active ingredient one or more proteins selected from the group consisting of the proteins listed in Table 11 and Table 12 or an agent for measuring the mRNA expression level thereof. Provides a composition for classification of papillary cancer (EFVPTC, Encapsulated FVPTC) and noninvasive follicular thyroid neoplasm with papillary-like nuclear feature (NIFTP).

[표 11][Table 11]

Figure pat00003
Figure pat00003

[표 12][Table 12]

Figure pat00004
Figure pat00004

본 발명의 일 구현예에서, 상기 조성물은 하기 표 13 및 표 14에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제를 더 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the composition may further include an agent for measuring the mRNA expression level of one or more proteins selected from the group consisting of proteins shown in Tables 13 and 14 below, but is not limited thereto. .

[표 13][Table 13]

Figure pat00005
Figure pat00005

Figure pat00006
Figure pat00006

Figure pat00007
Figure pat00007

Figure pat00008
Figure pat00008

Figure pat00009
Figure pat00009

[표 14][Table 14]

Figure pat00010
Figure pat00010

Figure pat00011
Figure pat00011

Figure pat00012
Figure pat00012

Figure pat00013
Figure pat00013

Figure pat00014
Figure pat00014

Figure pat00015
Figure pat00015

Figure pat00016
Figure pat00016

Figure pat00017
Figure pat00017

Figure pat00018
Figure pat00018

Figure pat00019
Figure pat00019

Figure pat00020
Figure pat00020

Figure pat00021
Figure pat00021

Figure pat00022
Figure pat00022

Figure pat00023
Figure pat00023

Figure pat00024
Figure pat00024

Figure pat00025
Figure pat00025

Figure pat00026
Figure pat00026

본 발명의 다른 구현예에서, 상기 mRNA의 발현 수준을 측정하는 제제는 상기 mRNA에 특이적으로 결합하는 프로브 또는 프라이머일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the agent for measuring the expression level of the mRNA may be a probe or primer that specifically binds to the mRNA, but is not limited thereto.

본 발명의 또 다른 구현예에서, 상기 단백질의 발현 수준을 측정하는 제제는 상기 단백질에 특이적인 항체 또는 앱타머일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the agent for measuring the expression level of the protein may be an antibody or aptamer specific for the protein, but is not limited thereto.

본 발명의 또 다른 구현예에서, 상기 조성물은 갑상선 수술 여부와 수술 범위를 결정하기 위한 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the composition may be used to determine whether or not to perform thyroid surgery and the extent of surgery, but is not limited thereto.

또한, 본 발명은 피검체의 시료에서 상기 표 11 및 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 단계를 포함하는, 침윤성 EFVPTC와 NIFTP의 분류에 필요한 정보를 제공하는 방법을 제공한다. In addition, the present invention provides information necessary for classification of invasive EFVPTC and NIFTP, comprising measuring the expression level of one or more proteins selected from the group consisting of the proteins shown in Tables 11 and 12 or mRNA expression levels in a sample of a subject. Provides a way to provide.

본 발명의 일 구현예에서, 상기 방법은 상기 표 11에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA의 발현이 검출되거나 또는 증가된 경우, NIFTP로 판정하는 단계를 더 포함할 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the method may further include determining NIFTP when the expression of one or more proteins selected from the group consisting of the proteins listed in Table 11 or mRNA thereof is detected or increased, It is not limited thereto.

본 발명의 다른 구현예에서, 상기 방법은 상기 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA의 발현이 검출되거나 또는 증가된 경우, 침윤성 EFVPTC로 판정하는 단계를 더 포함할 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the method may further include determining as invasive EFVPTC when the expression of one or more proteins selected from the group consisting of the proteins listed in Table 12 or mRNA thereof is detected or increased. , But is not limited thereto.

본 발명의 또 다른 구현예에서, 상기 시료는 혈액, 전혈, 혈장, 소변, 조직, 세포, 기관, 골수, 미세침 흡인 검체, 미세침 세척액, 중심부 생검 (core needle biopsy) 검체 및 타액으로 이루어진 군으로부터 선택된 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the sample is a group consisting of blood, whole blood, plasma, urine, tissue, cells, organs, bone marrow, fine needle aspiration specimen, fine needle washing liquid, core needle biopsy specimen, and saliva It may be one or more selected from, but is not limited thereto.

본 발명의 또 다른 구현예에서, 상기 단백질 발현 수준은 웨스턴 블랏, ELISA, 방사선면역분석, 방사선 면역 확산법, 오우크테로니 면역 확산법(Ouchterlony immunodiffusion), 로케트 면역전기영동(Rocket immunoelectrophoresis), 면역염색법, 면역침전 분석법, 보체 고정 분석법, 질량분석법(Mass spectrometry), FACS 및 단백질칩으로 이루어진 군으로부터 선택된 하나 이상의 방법으로 측정되는 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the protein expression level is Western blot, ELISA, radioimmunoassay, radioimmunoassay, Ouchterlony immunodiffusion, Rocket immunoelectrophoresis, immunostaining, It may be measured by one or more methods selected from the group consisting of immunoprecipitation assay, complement fixation assay, mass spectrometry, FACS, and protein chip, but is not limited thereto.

본 발명의 또 다른 구현예에서, 상기 mRNA 발현 수준은 PCR, RNase 보호 분석법, 노던 블랏팅(northern blotting), 사우던 블랏팅(southern blotting), In situ 교잡법 및 DNA 칩으로 이루어진 군으로부터 선택된 하나 이상의 방법으로 측정되는 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the mRNA expression level is one selected from the group consisting of PCR, RNase protection assay, northern blotting, southern blotting, in situ hybridization, and DNA chip. It may be measured by the above method, but is not limited thereto.

또한, 본 발명은 상기 표 11 및 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제를 유효성분으로 포함하는 침윤성 EFVPTC와 NIFTP의 분류용 키트를 제공한다.In addition, the present invention provides a kit for classification of invasive EFVPTC and NIFTP comprising as an active ingredient an agent for measuring the expression level of one or more proteins selected from the group consisting of the proteins described in Tables 11 and 12 or the mRNA expression level thereof.

또한, 본 발명은 상기 표 11 및 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제의 침윤성 EFVPTC와 NIFTP의 분류 용도를 제공한다.In addition, the present invention provides a classification use of invasive EFVPTC and NIFTP of an agent for measuring the expression level of one or more proteins selected from the group consisting of the proteins described in Tables 11 and 12, or the mRNA expression level thereof.

또한, 본 발명은 피검체의 시료에서 상기 표 11 및 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 단계를 포함하는, 침윤성 EFVPTC와 NIFTP의 분류 방법을 제공한다. In addition, the present invention provides a method for classifying invasive EFVPTC and NIFTP, comprising measuring the mRNA expression level of one or more proteins selected from the group consisting of the proteins shown in Tables 11 and 12 in a sample of a subject. .

본 발명은 침윤성 EFVPTC와 NIFTP의 분류용 바이오마커 조성물 및 이를 이용한 분류 방법에 관한 것으로, 이러한 바이오마커 조성물을 이용하여 수술 전에 침윤성 EFVPTC와 NIFTP를 명확히 진단하는 방법을 확립함으로써, 수술 없이 여포 변이 갑상선 유두암을 진단하고, 불필요한 수술 시행을 줄일 수 있을 것으로 기대된다.The present invention relates to a biomarker composition for classification of invasive EFVPTC and NIFTP and a classification method using the same, and by establishing a method for clearly diagnosing invasive EFVPTC and NIFTP before surgery using such a biomarker composition, follicular mutation thyroid papillary cancer without surgery It is expected to be able to diagnose and reduce unnecessary surgery.

도 1은 Multi-protease FASP 기법을 이용한 펩타이드 제조 공정을 나타낸 것이다.
도 2는 침윤성 EFVPTC와 NIFTP의 조직시료 단백질체 분석 결과를 나타낸 것이다.
도 3은 4번의 LC-MS/MS 수행에 대한 log10 raw protein intensity box plot 및 technical variation을 나타낸 correlation plot을 나타낸 것이다.
도 4는 4개 분석결과에 대한 클러스터링 결과를 나타낸 것이다
도 5는 Volcano plot을 통해 침윤성 EFVPTC와 NIFTP의 차별적 단백질을 나타낸 것이다.
도 6은 NIFTP에서 유의미하게 높게 발현되는 169개의 단백질의 ClueGO를 이용한 GO(Gene Ontology) 분석 결과를 나타낸 것이다.
도 7은 침윤성 EFVPTC에 유의미하게 높게 발현되는 237개 단백질의 ClueGO를 이용한 GO 분석 결과를 나타낸 것이다.
도 8은 침윤성 EFVPTC/NIFTP에 특이적인 단백질을 선별하기 위한 workflow를 도시한 것이다.1 shows a peptide manufacturing process using the Multi-protease FASP technique.
2 shows the results of proteomic analysis of tissue samples of invasive EFVPTC and NIFTP.
3 shows a log10 raw protein intensity box plot and a correlation plot showing technical variation for the 4 LC-MS/MS runs.
4 shows clustering results for four analysis results
5 shows the differential proteins of invasive EFVPTC and NIFTP through a Volcano plot.
Figure 6 shows the results of GO (Gene Ontology) analysis using ClueGO of 169 proteins that are significantly highly expressed in NIFTP.
7 shows the results of GO analysis using ClueGO of 237 proteins that are significantly highly expressed in invasive EFVPTC.
8 shows a workflow for selecting proteins specific for invasive EFVPTC/NIFTP.

본 발명은 하기 표 11 및 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제를 유효성분으로 포함하는 침윤성 피막형 여포 변이 갑상선 유두암(EFVPTC, Encapsulated FVPTC)과 유두암종유사핵모양비침습소포종양(NIFTP, noninvasive follicular thyroid neoplasm with papillary- like nuclear feature)의 분류용 조성물 및 그를 이용한 분류 방법 등을 제공한다.The present invention is an invasive capsular follicle mutant thyroid papillary carcinoma (EFVPTC, Encapsulated FVPTC) and nipples comprising as an active ingredient one or more proteins selected from the group consisting of the proteins listed in Table 11 and Table 12 or an agent for measuring the mRNA expression level thereof. A composition for classification of noninvasive follicular thyroid neoplasm with papillary-like nuclear feature (NIFTP) and a classification method using the same are provided.

이하, 본 발명에 대해 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명은 하기 표 11 및 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제를 유효성분으로 포함하는 침윤성 피막형 여포 변이 갑상선 유두암(EFVPTC, Encapsulated FVPTC)과 유두암종유사핵모양비침습소포종양(NIFTP, noninvasive follicular thyroid neoplasm with papillary- like nuclear feature)의 분류용 조성물에 관한 것이다.The present invention is an invasive capsular follicle mutant thyroid papillary carcinoma (EFVPTC, Encapsulated FVPTC) and nipples comprising as an active ingredient one or more proteins selected from the group consisting of the proteins listed in Table 11 and Table 12 or an agent for measuring the mRNA expression level thereof. It relates to a composition for classification of noninvasive follicular thyroid neoplasm with papillary-like nuclear feature (NIFTP).

[표 11][Table 11]

Figure pat00027
Figure pat00027

[표 12][Table 12]

Figure pat00028
Figure pat00028

본 발명에서, 상기 조성물은 하기 표 13 및 표 14에 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제를 더 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the composition may further include an agent for measuring the mRNA expression level of one or more proteins selected from the group consisting of proteins in Tables 13 and 14 below, but is not limited thereto.

[표 13][Table 13]

Figure pat00029
Figure pat00029

Figure pat00030
Figure pat00030

Figure pat00031
Figure pat00031

Figure pat00032
Figure pat00032

Figure pat00033
Figure pat00033

[표 14][Table 14]

Figure pat00034
Figure pat00034

Figure pat00035
Figure pat00035

Figure pat00036
Figure pat00036

Figure pat00037
Figure pat00037

Figure pat00038
Figure pat00038

Figure pat00039
Figure pat00039

Figure pat00040
Figure pat00040

Figure pat00041
Figure pat00041

Figure pat00042
Figure pat00042

Figure pat00043
Figure pat00043

Figure pat00044
Figure pat00044

Figure pat00045
Figure pat00045

Figure pat00046
Figure pat00046

Figure pat00047
Figure pat00047

Figure pat00048
Figure pat00048

Figure pat00049
Figure pat00049

Figure pat00050
Figure pat00050

본 발명에서, 상기 조성물은 갑상선 수술의 수행 여부와 수술 범위를 결정하는 용도로 사용될 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the composition may be used to determine whether to perform thyroid surgery and to determine the extent of surgery, but is not limited thereto.

본 발명에서, “갑상선 유두암”이란 갑상선 암 중에서 가장 흔한 종류로 전체 갑상선암 중 70% 정도를 차지하며 중년 여성에게 많이 발생하고, 비교적 치료에 잘 반응하며 예후도 좋은 것으로 알려져 있다. 유두암은 일반적으로 매우 천천히 자라며 예후도 좋은 편이다. 유두암은 갑상선의 한쪽엽(葉)에만 생길 수도 있지만 전체 유두암의 20~45%에서 양쪽 엽을 다 침범한 형태로 나타나고(다발성), 갑상선 주변 림프절(림프샘)로 번진 경우도 많게는 약 40%에서 관찰된다. 이런 경우 조기에 적절한 치료를 받으면 대부분 잘 치유되지만, 드물게는 폐나 뼈 등 다른 부위로 원격전이를 하는 예가 있으므로 조기 발견과 치료가 중요하다. 유두암의 경우, 갑상선의 한쪽 엽에서만 암이 발견되었더라도 수술전 초음파검사에서 피막침범이나 림프절 전이가 의심될 때에는 갑상선 전체를 제거하는 갑상선전절제술을 시행하며, 암이 중앙경부림프절을 침범하는 경우가 많기 때문에 갑상선전절제술을 시행할 때 대체로 갑상선과 중앙경부림프절을 함께 제거한다.In the present invention, the term "papillary thyroid cancer" is the most common type of thyroid cancer, accounting for about 70% of all thyroid cancers, and occurs frequently in middle-aged women, is known to be relatively well responsive to treatment and a good prognosis. Papillary cancer generally grows very slowly and has a good prognosis. Papillary cancer may occur only in one lobe of the thyroid gland, but in 20 to 45% of all papillary cancers, both lobes are invaded (multiple), and spread to lymph nodes (lymph glands) around the thyroid gland is also observed in as many as 40%. do. In this case, if appropriate treatment is received early, most of them heal well, but in rare cases, there are cases of distant metastasis to other parts such as lungs or bones, so early detection and treatment are important. In the case of papillary cancer, even if cancer is found in only one lobe of the thyroid gland, when encapsulation or lymph node metastasis is suspected on preoperative ultrasound, total thyroidectomy is performed to remove the entire thyroid gland, and the cancer often invades the central cervical lymph node. Therefore, when performing a total thyroidectomy, the thyroid gland and the central cervical lymph node are usually removed together.

본 발명에서, “EFVPTC”는 “Encapsulated Follicular Variant of Papillary Thyroid Carcinoma”의 약어로 피막성 여포 변이 유두 갑상선암을 나타낸다.In the present invention, “EFVPTC” is an abbreviation of “Encapsulated Follicular Variant of Papillary Thyroid Carcinoma” and refers to papillary thyroid cancer with encapsulated follicular mutation.

본 발명에서, “침윤성 EFVPTC”는 피막침윤, 혈관 침윤 등의 소견을 보이는 피막을 가지고 있는 FVPTC이다.In the present invention, "invasive EFVPTC" is an FVPTC having a film showing features such as film infiltration and vascular infiltration.

본 발명에서, “NIFTP(Non Invasive Follicular Thyroid neoplasm with Papillary-like nuclear feature)”는 과거 비침윤성 EFVPTC로 알려져 있었으며, 굉장히 좋은 예후를 보인다고 보고되었다. non invasive EFVPTC의 경우 109명의 환자 중 수술 후 추적기간(10-26년, median 13년) 중 재발이나 사망이 한 건도 없었다고 보고됨에 따라 non invasive EFVPTC를 Non Invasive Follicular Thyroid neoplasm with Papillary-like nuclear feature (NIFTP)로 개명하고 최근에 암 분류에서 제외하고, 경계성 종양으로 분류되었다. 또한, NIFTP는 임상적으로는 양성종양의 행동 양식을 따르고 매우 좋은 예후를 가지고 있어 단일결절의 경우 경과를 관찰하거나 갑상선반절제술로 충분한 치료가 되지만, 기본적으로 진단이 어렵고 대부분 수술 후에 세밀한 병리검사를 통해서만 진단이 이루어지므로 수술 전 수술 범위를 결정하기가 어렵다. 또한, NIFTP는 대부분 양호한 예후를 가지므로 외과의사의 관점에서 불필요한 갑상선전절제술을 피하는 것이 가장 중요한 점이 된다.In the present invention, "NIFTP (Non Invasive Follicular Thyroid neoplasm with Papillary-like nuclear feature)" was known as non-invasive EFVPTC in the past, and it has been reported to have a very good prognosis. In the case of non-invasive EFVPTC, no recurrence or death was reported during the postoperative follow-up period (10-26 years, median 13 years) among 109 patients, so non-invasive EFVPTC was used as Non Invasive Follicular Thyroid neoplasm with Papillary-like nuclear feature ( NIFTP) and recently excluded from cancer classification, and classified as borderline tumor. In addition, NIFTP clinically follows the behavioral pattern of benign tumors and has a very good prognosis. In the case of a single nodule, it is sufficient to observe the course or treat a thyroidectomy, but it is difficult to diagnose, and in most cases, detailed pathology examination is required after surgery. It is difficult to determine the scope of surgery before surgery because the diagnosis is made only through the diagnosis. In addition, since most of NIFTPs have a good prognosis, it is the most important point to avoid unnecessary total thyroidectomy from the point of view of the surgeon.

즉, 침윤성 EFVPTC와 NIFTP는 유전적으로 구별이 어려워, 수술이 비교적 불필요한 NIFTP 환자에게도 수술을 시행한다는 문제점이 있었다. 따라서, 수술이 필요한 침윤성 EFVPTC와 수술할 필요성이 높지 않은 NIFTP를 명확히 구분하고자, 본 발명을 완성하게 되었다.In other words, it is difficult to distinguish genetically between invasive EFVPTC and NIFTP, and there is a problem that surgery is performed even in patients with NIFTP who do not require surgery. Therefore, in order to clearly distinguish between invasive EFVPTC requiring surgery and NIFTP that does not require high surgery, the present invention has been completed.

본 발명에서는 침윤성 EFVPTC와 NIFTP를 분류하는 것이 목적이나, 이에 제한되는 것은 아니다. 갑상선 결절의 최종진단이 NIFTP인지 침윤성 EFVPTC인지에 따라 시험 항목이 달라지고 이에 따른 수술 여부, 수술 범위, 수술 후 치료방법까지 달라지므로, 이를 수술 전에 간편하고 정확하게 분류하는 것이 요구된다.In the present invention, it is an object to classify invasive EFVPTC and NIFTP, but is not limited thereto. Test items vary depending on whether the final diagnosis of thyroid nodule is NIFTP or invasive EFVPTC, and accordingly, whether or not surgery, scope of surgery, and treatment methods after surgery are different, it is required to classify them easily and accurately before surgery.

본 발명에서, “단백질”은 “폴리펩타이드(polypeptide)” 또는 “펩타이드(peptide)”와 호환성 있게 사용되며, 예컨대, 자연 상태의 단백질에서 일반적으로 발견되는 바와 같이 아미노산 잔기의 중합체를 말한다.In the present invention, "protein" is used interchangeably with "polypeptide" or "peptide", and, for example, refers to a polymer of amino acid residues as commonly found in proteins in a natural state.

본 발명에서, “발현(expression)”은 세포에서 단백질 또는 핵산이 생성되는 것을 의미한다. '단백질'은 '폴리펩타이드(polypeptide)' 또는 '펩타이드(peptide)'와 호환성 있게 사용되며, 예컨대, 자연 상태의 단백질에서 일반적으로 발견되는 바와 같이 아미노산 잔기의 중합체를 말한다. '폴리뉴클레오티드(polynucleotide)' 또는 '핵산'은 단일-또는 이중-가닥의 형태로 된 데옥시리보뉴클레오티드(DNA) 또는 리보뉴클레오티드(RNA)를 말한다. 다른 제한이 없는 한, 자연적으로 생성되는 뉴클레오티드와 비슷한 방법으로 핵산에 혼성화되는 자연적 뉴클레오티드의 공지된 아날로그도 포함된다. 'mRNA'는 단백질 합성 과정에서 특정 유전자로부터 아미노산 서열을 특정하게 되는 리보솜으로 유전 정보(유전자 특이적 염기 서열)를 전달하는 RNA를 의미한다.In the present invention, "expression" means that a protein or nucleic acid is produced in a cell. 'Protein' is used interchangeably with'polypeptide' or'peptide' and, for example, refers to a polymer of amino acid residues as commonly found in proteins in a natural state. 'Polynucleotide' or'nucleic acid' refers to deoxyribonucleotides (DNA) or ribonucleotides (RNA) in the form of single- or double-stranded. Unless otherwise limited, known analogues of natural nucleotides that hybridize to nucleic acids in a manner similar to those of naturally occurring nucleotides are also included. 'mRNA' refers to RNA that transfers genetic information (gene-specific nucleotide sequence) to ribosomes that specify amino acid sequences from specific genes in the process of protein synthesis.

본 발명에서 사용된 용어 “검출”은 목적하는 물질(본 발명에서의 마커 단백질)의 존재(발현) 여부를 측정 및 확인하는 것, 또는 목적하는 물질의 존재 수준(발현 수준)의 변화를 측정 및 확인하는 것을 모두 포함하는 의미이다. 같은 맥락에서, 본 발명에서 상기 단백질의 발현수준을 측정하는 것은 발현 여부를 측정하는 것(즉, 발현 유무를 측정하는 것), 또는 상기 단백질의 질적, 양적 변화 수준을 측정하는 것을 의미한다. 상기 측정은 정성적인 방법(분석)과 정량적인 방법을 모두 포함하여 제한 없이 수행될 수 있다. 단백질 수준의 측정에 있어서 정성적 방법과 정량적 방법의 종류는 당업계에 잘 알려져 있으며, 본 명세서에서 기술한 실험법들이 이에 포함된다. 각 방법 별로 구체적 단백질 수준 비교 방식은 당업계에 잘 알려져 있다. 따라서 상기 목적 단백질 검출은 표 1 내지 표 4의 단백질의 존재 여부 검출, 또는 상기 단백질 발현량의 증가(상향 조절) 또는 감소(하향 조절)를 확인하는 것을 포함하는 의미이다.The term "detection" used in the present invention is to measure and confirm the presence (expression) of a target substance (marker protein in the present invention), or to measure a change in the abundance level (expression level) of a target substance, and It is meant to include everything to check. In the same context, measuring the expression level of the protein in the present invention means measuring the expression or not (ie, measuring the presence or absence of expression), or measuring the level of qualitative or quantitative change of the protein. The measurement may be performed without limitation, including both a qualitative method (analysis) and a quantitative method. The types of qualitative and quantitative methods for measuring protein levels are well known in the art, and the experimental methods described herein are included therein. Specific protein level comparison methods for each method are well known in the art. Therefore, the detection of the target protein is meant to include detecting the presence or absence of the proteins in Tables 1 to 4, or confirming an increase (up-regulation) or decrease (down-regulation) of the protein expression level.

또한, 본 발명에서 사용된 용어 "진단"은 특정 질병 또는 질환에 대한 대상(subject)의 감수성(susceptibility)을 판정하는 것, 대상이 특정 질병 또는 질환을 현재 가지고 있는지 여부를 판정하는 것, 특정 질병 또는 질환에 걸린 대상의 예후(prognosis)를 판정하는 것, 또는 테라메트릭스(therametrics)(예컨대, 치료 효능에 대한 정보를 제공하기 위하여 객체의 상태를 모니터링하는 것)을 포함한다. In addition, the term "diagnosis" as used herein refers to determining the susceptibility of a subject to a specific disease or disease, determining whether the subject currently has a specific disease or disorder, or Or determining the prognosis of the diseased subject, or therametrics (eg, monitoring the condition of the subject to provide information on treatment efficacy).

본 발명의 조성물이 mRNA의 발현 수준을 측정하기 위한 것일 때에는 mRNA 발현 수준을 측정하는 제제는 mRNA에 특이적으로 결합하는 프로브 또는 프라이머 세트일 수 있다.When the composition of the present invention is for measuring the expression level of mRNA, the agent for measuring the mRNA expression level may be a set of probes or primers that specifically bind to mRNA.

상기 단백질의 mRNA 특이적인 프로브 또는 프라이머 세트를 포함하는 본 발명의 조성물은 공지된 RNA를 감지하는 방법에 필요한 제제를 추가로 포함할 수 있다. 본 조성물을 이용하여 공지된 RNA를 감지하는 방법을 제한없이 사용하여 피검체에서 상기 마커들의 mRNA의 수준을 측정할 수 있다.The composition of the present invention comprising the mRNA-specific probe or primer set of the protein may further contain an agent required for a known method of detecting RNA. Using the present composition, a known method for detecting RNA can be used without limitation to measure the level of the mRNA of the markers in a subject.

본 발명에서 "프라이머"는 짧은 자유 3말단 수산화기를 가지는 핵산 서열로 상보적인 주형 (template)과 염기쌍을 형성할 수 있고 템플레이트 가닥 복사를 위한 시작 지점으로 기능을 하는 짧은 핵산 서열을 의미한다. 프라이머는 적절한 완충용액 및 온도에서 중합반응 (즉, DNA 중합효소 또는 역전사효소)을 위한 시약 및 상이한 4가지 뉴클레오사이드 트리포스페이트의 존재하에서 DNA 합성을 개시할 수 있다.In the present invention, "primer" refers to a short nucleic acid sequence that is capable of forming a base pair with a complementary template with a nucleic acid sequence having a short free three-terminal hydroxyl group and serves as a starting point for template strand copying. Primers can initiate DNA synthesis in the presence of a reagent for polymerization (ie, DNA polymerase or reverse transcriptase) and four different nucleoside triphosphates at an appropriate buffer and temperature.

본 발명에서 "프로브"란 mRNA와 특이적 결합을 이룰 수 있는 짧게는 수 염기 내지 길게는 수백 염기에 해당하는 RNA 또는 DNA 등의 핵산 단편을 의미하며 표지 (Labelling)되어 있어서 특정 mRNA의 존재 유무를 확인할 수 있다. 프로브는 올리고 뉴클레오티드 프로브, 단쇄 DNA (single stranded DNA) 프로브, 이중쇄 DNA (double stranded DNA) 프로브, RNA 프로브 등의 형태로 제작될 수 있다. 적당한 프로브의 선택 및 혼성화 조건은 당업계에 공지된 것을 기초로 변형할 수 있다.In the present invention, "probe" refers to a nucleic acid fragment such as RNA or DNA corresponding to a few bases or hundreds of bases that can achieve specific binding to mRNA, and is labeled to determine the presence or absence of a specific mRNA. I can confirm. The probe may be manufactured in the form of an oligonucleotide probe, a single stranded DNA probe, a double stranded DNA probe, an RNA probe, or the like. Selection of suitable probes and conditions for hybridization can be modified based on those known in the art.

본 발명에서 상기 프라이머 또는 프로브는 포스포아미다이트(phosphoramidite) 고체지지체 합성법이나 기타 널리 공지된 방법을 이용하여 화학적으로 합성할 수 있다. 또한 프라이머 또는 프로브는 mRNA와의 혼성화를 방해하지 않는 범위에서 당해 기술 분야에 공지된 방법에 따라 다양하게 변형시킬 수 있다. 이러한 변형의 예로는 메틸화, 캡화, 천연 뉴클레오티드 하나 이상의 동족체로의 치환 및 뉴클레오티드 간의 변형, 예를 들면 하전되지 않은 연결체(예: 메틸 포스포네이트, 포스포트리에스테르, 포스포로아미데이트, 카바메이트 등) 또는 하전된 연결체(예: 포스포로티오에이트, 포스포로디티오에이트 등), 그리고 형광 또는 효소를 이용한 표지물질(labeling material)의 결합 등이 있다.In the present invention, the primer or probe may be chemically synthesized using a phosphoramidite solid support synthesis method or other well-known methods. In addition, primers or probes can be variously modified according to methods known in the art within a range that does not interfere with hybridization with mRNA. Examples of such modifications include methylation, encapsulation, substitution of one or more homologs of natural nucleotides, and modifications between nucleotides, such as uncharged linkers (e.g. methyl phosphonate, phosphotriester, phosphoroamidate, carbamate, etc.). ) Or charged linkers (eg, phosphorothioate, phosphorodithioate, etc.), and binding of a labeling material using fluorescence or enzymes.

한편, 본 발명에서 상기 단백질 발현 수준을 측정하는 제제는 상기 단백질에 특이적으로 결합하는 항체 또는 앱타머일 수 있다.Meanwhile, the agent for measuring the protein expression level in the present invention may be an antibody or aptamer that specifically binds to the protein.

본 발명에서, "항체"란 항원성 부위에 대해서 지시되는 특이적인 단백질 분자를 의미한다. 본 발명의 목적상, 항체는 마커 단백질에 대해 특이적으로 결합하는 항체를 의미하며, 다클론 항체, 단클론 항체 및 재조합 항체를 모두 포함한다. 또한 항원-항체 결합성을 갖는 것이면 전체 항체의 일부도 본 발명의 항체에 포함되며, 본 발명 단백질에 특이적으로 결합하는 모든 종류의 면역글로불린 항체가 포함된다. 예를 들어 2개의 전체 길이의 경쇄 및 2개의 전체 길이의 중쇄를 갖는 완전한 형태의 항체뿐 아니라 항체 분자의 기능적인 단편, 즉 항원 결합 기능을 갖는 Fab, F(ab'), F(ab')2 및 Fv 등을 포함한다. 나아가 본 발명의 항체에는 본 발명 단백질에 특이적으로 결합할 수 있는 것이라면 인간화 항체, 키메릭 항체 등의 특수 항체와 재조합 항체도 포함된다.In the present invention, "antibody" refers to a specific protein molecule directed against an antigenic site. For the purposes of the present invention, an antibody refers to an antibody that specifically binds to a marker protein, and includes all of polyclonal antibodies, monoclonal antibodies, and recombinant antibodies. In addition, as long as it has antigen-antibody binding, a part of the whole antibody is also included in the antibody of the present invention, and all kinds of immunoglobulin antibodies that specifically bind to the protein of the present invention are included. For example, a complete antibody having two full-length light chains and two full-length heavy chains, as well as functional fragments of antibody molecules, i.e., Fab, F(ab'), F(ab') with antigen-binding function 2 and Fv, and the like. Further, the antibody of the present invention includes special antibodies such as humanized antibodies and chimeric antibodies, and recombinant antibodies as long as it can specifically bind to the protein of the present invention.

본 발명에서 용어 “앱타머”는 시료 내의 검출하고자 하는 분석물질과 특이적으로 결합할 수 있는 물질로 그 자체로 안정된 삼차 구조를 가지는 단일 가닥 핵산(DNA, RNA, 또는 변형 핵산)을 의미하는 것으로, 특이적으로 시료 내의 표적 단백질의 존재를 확인할 수 있다. 앱타머의 제조는 일반적인 앱타머의 제조 방법에 따라, 확인하고자 하는 표적 단백질에 대해 선택적이고 높은 결합력을 가지는 올리고뉴클레오티드의 서열을 결정하여 합성한 후, 올리고뉴클레오티드의 5' 말단이나 3' 말단을 앱타머 칩의 관능기에 결합할 수 있도록, -SH, -COOH, -OH 또는 NH2로 변형을 시킴으로써 이루어질 수 있으나, 이에 제한되지 않는다.In the present invention, the term “aptamer” refers to a single-stranded nucleic acid (DNA, RNA, or modified nucleic acid) having a stable tertiary structure as a substance capable of specifically binding to an analyte to be detected in a sample. , Specifically, the presence of the target protein in the sample can be confirmed. The production of aptamer is synthesized by determining the sequence of an oligonucleotide having a high binding ability and selective to the target protein to be identified according to a general production method of aptamer, and then applying the 5'or 3'end of the oligonucleotide. In order to bind to the functional group of the timer chip, it may be made by modifying it with -SH, -COOH, -OH or NH 2 , but is not limited thereto.

상기 단백질 특이적인 항체를 포함하는 본 발명의 조성물은 공지된 단백질을 감지하는 방법에 필요한 제제를 추가적으로 포함할 수 있으며, 본 조성물을 이용하여 공지된 단백질을 감지하는 방법을 제한없이 사용하여 피검체(본 발명에서는 피검체로부터 수득한 생물학적 시료)에서 단백질의 발현 수준을 측정할 수 있다.The composition of the present invention containing the protein-specific antibody may additionally include an agent required for a method of detecting a known protein, and a subject ( In the present invention, the expression level of a protein can be measured in a biological sample obtained from a subject).

본 발명의 유전자는 핵산 서열이 유전자 은행에 등록되어 있으므로 당업자는 상기 서열을 바탕으로 이들 유전자의 특정 영역을 특이적으로 증폭하는 안티센스 올리고뉴클레오티드, 프라이머 쌍 또는 프로브를 디자인할 수 있다.Since the nucleic acid sequence of the gene of the present invention is registered in the gene bank, those skilled in the art can design antisense oligonucleotides, primer pairs, or probes that specifically amplify specific regions of these genes based on the above sequences.

본 발명의 안티센스 올리고뉴클레오티드, 프라이머 또는 프로브는 포스포르 아미다이트 고체 지지체 방법, 또는 기타 널리 공지된 방법을 사용하여 화학적으로 합성할 수 있다. 이러한 핵산 서열은 또한 당해 분야에 공지된 많은 수단을 이용하여 변형시킬 수 있다. 이러한 변형의 비-제한적인 예로는 메틸화, 캡화, 천연 뉴클레오티드 하나 이상의 동족체로의 치환, 및 뉴클레오티드 간의 변형, 예를 들면, 하전되지 않은 연결체 (예: 메틸 포스포네이트, 포스포트리에스테르, 포스포로아미 데이트, 카바메이트 등) 또는 하전된 연결체 (예: 포스포로티오에이트, 포스포로디티오에이트 등)로의 변형이 있다.Antisense oligonucleotides, primers, or probes of the present invention can be chemically synthesized using the phosphor amidite solid support method, or other well known methods. Such nucleic acid sequences can also be modified using a number of means known in the art. Non-limiting examples of such modifications include methylation, encapsulation, substitution of one or more homologs of natural nucleotides, and modifications between nucleotides, such as uncharged linkers (e.g., methyl phosphonate, phosphotriester, phosphoro Amidates, carbamates, etc.) or to charged linkers (e.g. phosphorothioate, phosphorodithioate, etc.).

"기능적 등가물"이라는 용어는 예를 들어, 기준(reference) 서열로부터 하나 또는 그 이상의 치환, 결실 또는 부가, 기준(reference) 서열과 실험(subject) 서열 사이의 다양한 기능적 비유사성을 낳지 않는 실제 효과(net effect) 등 변화된 돌연변이 서열의 뉴클레오티드와 핵산서열 모두를 의미한다. 통상적으로, 그런 실질적 등가물인 서열은 단지 약 35%(즉, 실질적으로 등가적인 서열에서의 각 잔기 치환, 부가 및 결실의 숫자는 상응하는 기준 서열과 비교하고 실질적으로 등가적인 서열에서의 나머지 전체 숫자로 나누었을 때 약 0.35 또는 그 이하이다) 정도로 본 명세서에 나열된 것에서부터 다양하다. 그런 서열은 나열된 서열과 65%의 서열 동일성을 갖는다. 본 발명에 따른 실질적 등가물인, 예를 들어 돌연변이, 아미노산 서열은 나열된 아미노산 서열과 바람직하게는 최소한 80%의 서열 동일성, 보다 바람직하게는 최소한 90%의 서열 동일성을 갖는다. 실질적 등가물인 본 발명의 뉴클레오티드 서열은 예를 들어, 유전자 암호의 중복(redundancy) 또는 축퇴(degeneracy)를 고려할 때, 더 낮은 백분율의 서열 동일성을 가질 수 있다. 바람직하게는, 뉴클레오티드 서열은 최소한 약 65%의 동일성, 보다 바람직하게는 최소한 약 75%의 동일성, 가장 바람직하게는 약 95%의 동일성을 가져야 한다. 본 발명의 목적을 위해서는, 실질적으로 등가적인 생물학적 활성과 실질적으로 등가적인 합성 특징을 가지는 서열들은 실질적 등가물로 취급된다. 등가물을 결정하기 위해, 성숙 서열(예를 들어, 위(spurious) 종결코돈(stop codon)을 제조하는 돌연변이를 통한)의 절단(truncation)은 무시되어야 한다.The term "functional equivalent" refers to, for example, one or more substitutions, deletions or additions from a reference sequence, a real effect that does not result in various functional dissimilarities between the reference sequence and the subject sequence ( net effect) refers to both nucleotide and nucleic acid sequences of mutant sequences. Typically, such a substantially equivalent sequence is only about 35% (i.e., the number of substitutions, additions, and deletions of each residue in the substantially equivalent sequence is compared to the corresponding reference sequence and the remaining total number in the substantially equivalent sequence. Divided by about 0.35 or less), it varies from those listed in this specification. Such sequences have 65% sequence identity with the listed sequences. Substantially equivalents according to the invention, for example mutant, amino acid sequences have preferably at least 80% sequence identity, more preferably at least 90% sequence identity with the listed amino acid sequence. Substantially equivalent nucleotide sequences of the invention may have a lower percentage of sequence identity, for example, taking into account the redundancy or degeneracy of the genetic code. Preferably, the nucleotide sequence should have at least about 65% identity, more preferably at least about 75% identity, and most preferably about 95% identity. For the purposes of the present invention, sequences having substantially equivalent biological activity and substantially equivalent synthetic characteristics are treated as substantial equivalents. In order to determine the equivalent, the truncation of the mature sequence (eg, through a mutation producing a spurious stop codon) should be ignored.

또한, 본 발명은 피검체의 시료에서 상기 표 11 및 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 단계를 포함하는, 침윤성 EFVPTC와 NIFTP의 분류에 필요한 정보를 제공하는 방법을 제공한다.In addition, the present invention provides information necessary for classification of invasive EFVPTC and NIFTP, comprising measuring the expression level of one or more proteins selected from the group consisting of the proteins shown in Tables 11 and 12 or mRNA expression levels in a sample of a subject. Provides a way to provide.

본 발명에서, 상기 방법은 상기 표 11에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA의 발현이 검출되거나 또는 증가된 경우, NIFTP로 판정하는 단계를 더 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the method may further include determining as NIFTP when the expression of one or more proteins selected from the group consisting of proteins described in Table 11 or mRNA thereof is detected or increased, but is limited thereto. no.

본 발명에서, 상기 방법은 상기 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA의 발현이 검출되거나 또는 증가된 경우, 침윤성 EFVPTC로 판정하는 단계를 더 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the method may further include determining as invasive EFVPTC when the expression of one or more proteins selected from the group consisting of the proteins listed in Table 12 or mRNA thereof is detected or increased, but is limited thereto. It is not.

본 발명의 일 실시예에서, 상기 피검체는 갑상선 결절 또는 갑상선암 환자일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the subject may be a thyroid nodule or thyroid cancer patient, but is not limited thereto.

본 발명에서 용어 ‘분석’은 바람직하게 ‘측정’을 의미하는 것일 수 있고, 상기 정성분석은 목적하는 물질의 존재 여부를 측정 및 확인하는 것을 의미하는 것일 수 있으며, 상기 정량분석은 목적하는 물질의 존재 수준(발현 수준) 또는 양의 변화를 측정 및 확인하는 것을 의미하는 것일 수 있다. 본 발명에서 분석 또는 측정은 정성적인 방법과 정량적인 방법을 모두 포함하여 제한없이 수행될 수 있으며, 바람직하게는 정량적인 측정이 수행되는 것일 수 있다.In the present invention, the term'analysis' may preferably mean'measurement', the qualitative analysis may mean measuring and confirming the presence or absence of a target substance, and the quantitative analysis It may mean measuring and confirming a change in the level of presence (level of expression) or quantity. In the present invention, the analysis or measurement may be performed without limitation, including both a qualitative method and a quantitative method, and preferably, a quantitative measurement may be performed.

상기 생물학적 시료는 갑상선 결절 또는 갑상선암 환자의 진단을 분류하고자 하는 피검체에서 채취된 것이면 제한 없이 사용할 수 있으며, 예를 들어 생검 등으로 얻어진 조직, 세포, 혈액, 혈장, 혈청, 타액, 비액, 객담, 관절낭액, 양수, 복수, 자궁경부 분비물, 질 분비물, 소변, 뇌척수액 등 생체 시료 뿐만 아니라 미세침 흡인 검체 및 미세침 세척액 또한 포함한다. 바람직하게는 생물학적 액체 시료, 예를 들어 혈액, 전혈, 혈장, 소변, 조직, 세포, 기관, 골수, 미세침 흡인 검체, 미세침 세척액, 중심부 생검 (core needle biopsy) 검체 및 타액으로 이루어진 군에서 선택된 하나 이상에서 측정될 수 있다. 본 발명은 갑상선 결절 또는 갑상선암이 발생된 직접적 갑상선 병변조직 외의 체액시료(일례로, 혈장)를 통해 진단이 가능하여, 진단의 효용성, 신속성, 편이성 및 안전성 등이 증가된다는 점에서 기술적 의의가 크다. The biological sample may be used without limitation as long as it is collected from a subject to be classified as a thyroid nodule or thyroid cancer patient.For example, tissues, cells, blood, plasma, serum, saliva, nasal fluid, sputum, obtained by biopsy, etc. It includes not only biological samples such as joint capsule fluid, amniotic fluid, ascites, cervical secretions, vaginal secretions, urine, cerebrospinal fluid, etc., but also microneedle aspiration samples and microneedle wash solutions. Preferably, a biological liquid sample, for example, blood, whole blood, plasma, urine, tissue, cells, organs, bone marrow, fine needle aspiration specimen, fine needle wash, core needle biopsy specimen and saliva selected from the group consisting of It can be measured in more than one. The present invention can be diagnosed through a body fluid sample (e.g., plasma) other than a thyroid nodule or thyroid cancer-generated direct thyroid lesion tissue, thereby increasing the effectiveness, rapidity, convenience, and safety of diagnosis.

본 발명에서, “갑상선 미세침 흡인 검사(FNAC; fine needle aspiration cytology)”란 초음파를 보면서 의심되는 갑상선(경부) 결절을 미세한 주사바늘로 찔러 소량의 세포를 얻은 후 양성 혹은 악성의 세포 진단을 목적으로 시행되며, 가느다란 주사 바늘로 결절을 찔러 세포를 흡인함으로써 갑상선 수술의 진행 여부, 수술 범위 및 림프절 절제 범위 등을 결정하는 기준이 된다.In the present invention, the term "fine needle aspiration cytology (FNAC)" is intended to diagnose benign or malignant cells after acquiring a small amount of cells by stabbing a suspected thyroid (neck) nodule while viewing ultrasound It is a standard for determining the progression of thyroid surgery, the extent of surgery, and the extent of lymph node resection by aspirating cells by piercing the nodule with a thin injection needle.

상기 시료는 검출 또는 진단에 사용하기 전에 전처리할 수 있다. 예를 들어, 균질화(homogenization), 여과, 증류, 추출, 농축, 방해 성분의 불활성화, 시약의 첨가 등을 포함할 수 있다. 상기 시료는 단백질 마커의 탐지 감도를 증가시키도록 준비될 수 있는데 예를 들어 환자로부터 수득한 혈청 시료는 음이온 교환 크로마토그래피, 친화도 크로마토그래피, 크기별 배제 크로마토그래피(size exclusion chromatography), 액체 크로마토그래피, 연속추출(sequential extraction) 또는 젤 전기영동 등의 방법을 이용하여 전처리될 수 있다.The sample can be pretreated prior to use for detection or diagnosis. For example, it may include homogenization, filtration, distillation, extraction, concentration, inactivation of interfering components, addition of reagents, and the like. The sample may be prepared to increase the detection sensitivity of the protein marker. For example, a serum sample obtained from a patient is anion exchange chromatography, affinity chromatography, size exclusion chromatography, liquid chromatography, It can be pretreated using a method such as sequential extraction or gel electrophoresis.

상기 단백질 발현 수준 측정은 당업계에 공지된 단백질 발현 측정 방법에 의한 것이라면 측정 방법이 특별히 제한되지 않으나, 예를 들어 웨스턴 블랏, ELISA, 방사선면역분석, 방사선 면역 확산법, 오우크테로니 면역 확산법(Ouchterlony immunodiffusion), 로케트 면역전기영동(Rocket immunoelectrophoresis), 면역염색법, 면역침전 분석법, 보체 고정 분석법, 질량분석법(Mass spectrometry), FACS 및 단백질칩으로 이루어진 군으로부터 선택된 하나 이상일 수 있다.The measurement of the protein expression level is not particularly limited as long as it is by a protein expression measurement method known in the art.For example, Western blot, ELISA, radioimmunoassay, radioimmune diffusion method, Ouchterlony immune diffusion method (Ouchterlony immunodiffusion), rocket immunoelectrophoresis, immunostaining, immunoprecipitation assay, complement fixation assay, mass spectrometry, FACS, and protein chip.

상기 유전자 발현 수준 측정은 당업계에 공지된 유전자 발현 측정 방법에 의한 PCR, RNase 보호 분석법, 노던 블랏팅(northern blotting), 사우던 블랏팅(southern blotting), In situ 교잡법 및 DNA 칩으로 이루어진 군으로부터 선택된 하나 이상일 수 있다.The gene expression level measurement is a group consisting of PCR, RNase protection assay, northern blotting, southern blotting, in situ hybridization, and DNA chip according to a gene expression measurement method known in the art. It may be one or more selected from.

또한, 본 발명은 상기 표 11 및 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제를 유효성분으로 포함하는 침윤성 EFVPTC와 NIFTP의 분류용 키트를 제공한다.In addition, the present invention provides a kit for classification of invasive EFVPTC and NIFTP comprising as an active ingredient an agent for measuring the expression level of one or more proteins selected from the group consisting of the proteins described in Tables 11 and 12 or the mRNA expression level thereof.

본 발명의 키트에는 표적 단백질을 마커로 인식하는 항체 또는 mRNA를 마커로 인식하는 프라이머, 프로브뿐만 아니라 분석 방법에 적합한 한 종류 또는 그 이상의 다른 구성 성분 조성물, 용액 또는 장치가 포함될 수 있다.The kit of the present invention may include an antibody that recognizes a target protein as a marker or a primer, a probe that recognizes an mRNA as a marker, as well as one or more other constituent compositions, solutions, or devices suitable for an analysis method.

구체적인 양태로서 상기 진단 키트는 역전사 중합효소반응을 수행하기 위해 필요한 필수 요소를 포함하는 것을 특징으로 하는 진단용 키트일 수 있다. 역전사 중합효소반응 키트는 마커 유전자에 대한 특이적인 각각의 프라이머 쌍을 포함한다. 프라이머는 각 마커 유전자의 핵산서열에 특이적인 서열을 가지는 뉴클레오타이드로서, 약 7bp 내지 50bp의 길이, 보다 바람직하게는 약 10bp 내지 30bp의 길이이다. 또한 대조군 유전자의 핵산 서열에 특이적인 프라이머를 포함할 수 있다. 그 외 역전사 중합효소반응 키트는 테스트 튜브 또는 다른 적절한 컨테이너, 반응 완충액(pH 및 마그네슘 농도는 다양), 데옥시뉴클레오타이드(dNTPs), Taq-폴리머라아제 및 역전사효소와 같은 효소, DNAse, RNAse 억제제 DEPC-수(DEPC-water), 멸균수 등을 포함할 수 있다. As a specific embodiment, the diagnostic kit may be a diagnostic kit comprising essential elements necessary to perform a reverse transcription polymerase reaction. The reverse transcription polymerase reaction kit includes each primer pair specific for a marker gene. The primer is a nucleotide having a sequence specific to the nucleic acid sequence of each marker gene, and is about 7 bp to 50 bp in length, more preferably about 10 bp to 30 bp in length. In addition, a primer specific to the nucleic acid sequence of the control gene may be included. Other reverse transcription polymerase reaction kits include test tubes or other suitable containers, reaction buffers (various pH and magnesium concentrations), deoxynucleotides (dNTPs), enzymes such as Taq-polymerase and reverse transcriptase, DNAse, RNAse inhibitors DEPC. -May include DEPC-water, sterilized water, etc.

또 다른 양태로는 DNA 칩을 수행하기 위해 필요한 필수 요소를 포함하는 것을 특징으로 하는 진단 키트일 수 있다. DNA 칩 키트는 유전자 또는 그의 단편에 해당하는 cDNA 또는 올리고뉴클레오티드(oligonucleotide)가 부착되어 있는 기판, 및 형광표식 프로브를 제작하기 위한 시약, 제제, 효소 등을 포함할 수 있다. 또한 기판은 대조군 유전자 또는 그의 단편에 해당하는 cDNA 또는 올리고뉴클레오티드를 포함할 수 있다. In another aspect, it may be a diagnostic kit characterized in that it contains the essential elements necessary to perform the DNA chip. The DNA chip kit may include a substrate to which cDNA or oligonucleotide corresponding to a gene or fragment thereof is attached, and reagents, agents, enzymes, etc. for preparing a fluorescently labeled probe. In addition, the substrate may include a cDNA or oligonucleotide corresponding to a control gene or a fragment thereof.

본 발명에서 사용되는 용어는 본 발명에서의 기능을 고려하면서 가능한 현재 널리 사용되는 일반적인 용어들을 선택하였으나, 이는 당 분야에 종사하는 기술자의 의도 또는 판례, 새로운 기술의 출현 등에 따라 달라질 수 있다. 또한, 특정한 경우는 출원인이 임의로 선정한 용어도 있으며, 이 경우 해당되는 발명의 설명 부분에서 상세히 그 의미를 기재할 것이다. 따라서 본 발명에서 사용되는 용어는 단순한 용어의 명칭이 아닌, 그 용어가 가지는 의미와 본 발명의 전반에 걸친 내용을 토대로 정의되어야 한다.Terms used in the present invention have selected general terms that are currently widely used as possible while taking functions of the present invention into consideration, but this may vary according to the intention or precedent of a technician working in the field, the emergence of new technologies, and the like. In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meaning of the terms will be described in detail in the description of the corresponding invention. Therefore, the terms used in the present invention should be defined based on the meaning of the term and the overall contents of the present invention, not a simple name of the term.

본 발명의 명세서 전체에서, 어떤 부분이 어떤 구성 요소를 "포함" 한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다. 본 발명의 명세서 전체에서 사용되는 정도의 용어 "약", "실질적으로" 등은 언급된 의미에 고유한 제조 및 물질 허용오차가 제시될 때 그 수치에서 또는 그 수치에 근접한 의미로 사용되고, 본 발명의 이해를 돕기 위해 정확하거나 절대적인 수치가 언급된 개시 내용을 비양심적인 침해자가 부당하게 이용하는 것을 방지하기 위해 사용된다. Throughout the specification of the present invention, when a certain part "includes" a certain constituent element, it means that other constituent elements may be further included rather than excluding other constituent elements unless otherwise stated. The terms "about", "substantially", etc. of the degree used throughout the specification of the present invention are used at or close to the numerical value when manufacturing and material tolerances specific to the stated meaning are presented, and the present invention To aid in understanding of, accurate or absolute figures are used to prevent unreasonable use of the stated disclosure by unscrupulous infringers.

본 발명의 명세서 전체에서, 마쿠시 형식의 표현에 포함된 "이들의 조합"의 용어는 마쿠시 형식의 표현에 기재된 구성 요소들로 이루어진 군에서 선택되는 하나 이상의 혼합 또는 조합을 의미하는 것으로서, 상기 구성 요소들로 이루어진 군에서 선택되는 하나 이상을 포함하는 것을 의미한다.In the entire specification of the present invention, the term "combination of these" included in the expression of the Makushi format refers to one or more mixtures or combinations selected from the group consisting of the constituent elements described in the expression of the Makushi format. It means to include at least one selected from the group consisting of constituent elements.

이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, a preferred embodiment is presented to aid the understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the contents of the present invention are not limited by the examples.

[실시예][Example]

실험 준비Preparation for experiment

1. 시료 준비1. Sample preparation

NIFTP와 침윤성 EFVPTC의 pooled 조직 시료에서 단백질체 분석을 수행하였으며, 조직 시료는 수술 직후 신선 동결 조직으로 보관된 것을 이용하였다. Proteomic analysis was performed on pooled tissue samples of NIFTP and invasive EFVPTC, and tissue samples were stored as fresh frozen tissue immediately after surgery.

도 1에 나타난 바와 같이, 조직 시료를 30 KDa cutoff filter unit을 digestion unit로 사용하는 FASP (Filter-aided sample prepation)기법과 digestion 효율이 매우 우수한 MS grade LysS/Trypsin mixture protease를 Protein:protease = 25:1를 이용하여 펩타이드를 제조하였다. As shown in FIG. 1, a FASP (Filter-aided sample prepation) technique using a 30 KDa cutoff filter unit as a digestion unit for a tissue sample and MS grade LysS/Trypsin mixture protease with very excellent digestion efficiency Protein:protease = 25: Peptide was prepared using 1.

펩타이드를 용해(lysis)한 후에 FASP (Filter-aided sample preparation) 기법을 이용하여 펩타이드를 제조 후 고분해능 질량분석기를 이용하여 spectrum을 획득하였으며, Database search 및 통계 분석을 수행하였다.After lysis of the peptide, the peptide was prepared using a filter-aided sample preparation (FASP) technique, and a spectrum was obtained using a high-resolution mass spectrometer, and a database search and statistical analysis were performed.

2. LC-MS 분석2. LC-MS analysis

MS장비는 Q-Exactive Plus BioPharm version (Thermo, USA)을, LC는 UltiMate™ 3000 RSLCnano System (Thermo, USA)를 사용하였다. 펩타이드 시료는 5ul씩 injection하여 350nl/min의 유속으로 NanoLC와 연동된 Ion trap mass spectrometer로 분석을 수행하였다.The MS equipment was Q-Exactive Plus BioPharm version (Thermo, USA), and the LC was UltiMate™ 3000 RSLCnano System (Thermo, USA). Peptide samples were injected every 5ul and analyzed with an ion trap mass spectrometer linked to NanoLC at a flow rate of 350nl/min.

LC는 Solution A (5% acetonitrile, 0.1% formic acid)와 solution B (95% acetonitrile, 0.1% formic acid)의 농도 구배 120분을 포함하여 총 150분 동안 분리하였다. 사용하는 분석 컬럼은 AQUA C18 (5um, 125A)을 충진한 내직경 75um, 외직경 360um, 길이 50cm fused silica capillary column를 사용하여 펩타이드 혼합체를 분리하였다. LC was separated for a total of 150 minutes, including the concentration gradient of Solution A (5% acetonitrile, 0.1% formic acid) and Solution B (95% acetonitrile, 0.1% formic acid) for 120 minutes. The peptide mixture was separated using a fused silica capillary column with an inner diameter of 75 um, an outer diameter of 360 um, and a length of 50 cm filled with AQUA C18 (5 um, 125A).

분리된 펩타이드는 2000V의 Electrospray ionization voltage을 이용하여 이온 분사하며 이온방출기(ion emitter)는 내직경 20um tappered ion spray emitter를 통해 질량분석기로 주입하여 스펙트럼 데이터를 획득하였다.The separated peptide was ion-sprayed using an electrospray ionization voltage of 2000V, and the ion emitter was injected into a mass spectrometer through a 20um inner diameter tappered ion spray emitter to obtain spectral data.

Orbitrap MS 분석은 400~2000 m/z 범위에 대해 Ion trap MS로 1번의 survey scan (resolution 30,000)후에 Higher energy collision dissociation (HCD, 25% energy level) 방식을 이용하여 Orbitrap MS를 이용하고, 8번의 MS/MS (resolution 60,000)분석을 수행하였다.Orbitrap MS analysis is performed with Ion trap MS for the range of 400 to 2000 m/z, using the Higher energy collision dissociation (HCD, 25% energy level) method after one survey scan (resolution 30,000) using Orbitrap MS. MS/MS (resolution 60,000) analysis was performed.

5분의 dynamic exclusion option을 통해 중복된 펩타이드 ion 검출을 최소화였으며, Ion trap의 Auto gain control target setting은 Full MS에 대해서는 3E04를, FT MS/MS에 대해서는 2E5을 사용하였다.The detection of duplicated peptide ions was minimized through the dynamic exclusion option of 5 minutes, and the auto gain control target setting of the ion trap was 3E04 for Full MS and 2E5 for FT MS/MS.

3. 데이터베이스 분석 3. Database Analysis

2번 반복 측정한 RAW file을 Sequest algorithm 기반의 데이터베이스 분석 software인 Proteome Discoverer (Thermo, USA, version 2.2)를 이용하여 정성 분석 및 Label free 정량 분석을 수행하였다. The RAW file measured twice was subjected to qualitative analysis and label free quantitative analysis using Proteome Discoverer (Thermo, USA, version 2.2), a database analysis software based on Sequest algorithm.

펩타이드 변형(modification)은 시스테인 카바미도메틸화(cystein carbamidomethylation)를 고정된 변형으로 설정하고 N-말단 아세틸화, 메티오닌 산화(methionine oxidation), 포스포- 세린(phospho- serine), -트레오닌, 및 -티로신은 다양한 변형으로 설정하여 수행하였다. Peptide modifications set cystein carbamidomethylation as a fixed modification and N-terminal acetylation, methionine oxidation, phospho-serine, -threonine, and -tyrosine. Was performed by setting various modifications.

트립신 미스 절단(Trypsin miss cleavage)은 “1” 값을 이용하였으며, Trypsin miss cleavage was used as a value of “1”,

서열데이터베이스는 2017년 7월에 다운로드 받은 swissprot sequence DB를 사용하였다. The sequence database used the swissprot sequence DB downloaded in July 2017.

4. Bioinformatics 및 통계 분석4. Bioinformatics and statistical analysis

동정된 단백체들을 Uniprot accession number를 query로 사용하여 ClueGO 프로그램을 이용하였으며, gene ontology (GO)를 분석하였다. The identified proteins were used as a query using the Uniprot accession number as a query, and the ClueGO program was used, and gene ontology (GO) was analyzed.

R 프로그램을 활용하여 heatmap 및 clustering 분석과 volcano plot 분석을 수행하였다. Heatmap and clustering analysis and volcano plot analysis were performed using the R program.

실시예 1. NIFTP와 침윤성 EFVPTC의 조직시료에서 차별적으로 발현되는 단백질 바이오마커 선별Example 1. Selection of protein biomarkers differentially expressed in tissue samples of NIFTP and invasive EFVPTC

NIFTP와 침윤성 EFVPTC의 조직시료의 단백체를 고분해능 질량분석기를 이용하여 단백질체를 정성, 정량 분석을 수행한 결과, 도 2에 나타난 바와 같이, venn diagram의 형태로 총 3,972개의 갑상선 조직 단백질들을 발굴하였다. As a result of qualitative and quantitative analysis of the protein bodies of the tissue samples of NIFTP and invasive EFVPTC using a high-resolution mass spectrometer, as shown in FIG. 2, a total of 3,972 thyroid tissue proteins were discovered in the form of a venn diagram.

NIFTP 조직에서는 3,792개, 침윤성 EFVPTC 조직에서는 3,788개의 단백질들이 동정되었다.3,792 proteins were identified in NIFTP tissues and 3,788 proteins in invasive EFVPTC tissues.

이중 두 개의 조직에서 공통되게 3,608개가 동정되었고 NIFTP 조직 특이적으로 184개 단백질이, 침윤성 EFVPTC 조직 특이적으로 180개 단백질이 정성분석 되었다. Of these, 3,608 were identified in common in two tissues, 184 proteins were specifically analyzed for NIFTP tissues, and 180 proteins were specifically analyzed for invasive EFVPTC tissues.

침윤성 EFVPTC에서만 동정되고 NIFTP에서는 검출되지 않은 단백질들을 표 1에 기재하였으며, Proteins identified only in invasive EFVPTC and not detected in NIFTP are listed in Table 1.

NIFTP에서만 동정되고 침윤성 EFVPTC에서는 검출되지 않은 단백질들을 표 2에 기재하였다.Proteins identified only in NIFTP and not detected in invasive EFVPTC are listed in Table 2.

침윤성 EFVPTC에서만 동정되고 NIFTP에서는 검출되지 않은 단백질Protein identified only in invasive EFVPTC but not detected in NIFTP InformationInformation Found in Sample GroupFound in Sample Group AccessionAccession ProteinNameProteinName GeneNameGeneName EFVPTCEFVPTC NIFTPNIFTP P35579-2P35579-2 Isoform 2 of Myosin-9Isoform 2 of Myosin-9 MYH9MYH9 HighHigh Not FoundNot Found P01889P01889 HLA class I histocompatibility antigen, B-7 alpha chainHLA class I histocompatibility antigen, B-7 alpha chain HLA-BHLA-B HighHigh Not FoundNot Found P61978-2P61978-2 Isoform 2 of Heterogeneous nuclear ribonucleoprotein KIsoform 2 of Heterogeneous nuclear ribonucleoprotein K HNRNPKHNRNPK HighHigh Not FoundNot Found P50993P50993 Sodium/potassium-transporting ATPase subunit alpha-2Sodium/potassium-transporting ATPase subunit alpha-2 ATP1A2ATP1A2 HighHigh Not FoundNot Found P30499P30499 HLA class I histocompatibility antigen, Cw-1 alpha chainHLA class I histocompatibility antigen, Cw-1 alpha chain HLA-CHLA-C HighHigh Not FoundNot Found Q9H9G7Q9H9G7 Protein argonaute-3Protein argonaute-3 AGO3AGO3 HighHigh Not FoundNot Found P0CG39P0CG39 POTE ankyrin domain family member JPOTE ankyrin domain family member J POTEJPOTEJ HighHigh Not FoundNot Found Q96PK6-5Q96PK6-5 Isoform 5 of RNA-binding protein 14Isoform 5 of RNA-binding protein 14 RBM14RBM14 HighHigh Not FoundNot Found Q8NFP9Q8NFP9 NeurobeachinNeurobeachin NBEANBEA HighHigh Not FoundNot Found Q8N474Q8N474 Secreted frizzled-related protein 1Secreted frizzled-related protein 1 SFRP1SFRP1 HighHigh Not FoundNot Found P63172P63172 Dynein light chain Tctex-type 1Dynein light chain Tctex-type 1 DYNLT1DYNLT1 HighHigh Not FoundNot Found Q16576-2Q16576-2 Isoform 2 of Histone-binding protein RBBP7Isoform 2 of Histone-binding protein RBBP7 RBBP7RBBP7 HighHigh Not FoundNot Found Q9UQP3Q9UQP3 Tenascin-NTenascin-N TNNTNN HighHigh Not FoundNot Found Q96F07Q96F07 Cytoplasmic FMR1-interacting protein 2Cytoplasmic FMR1-interacting protein 2 CYFIP2CYFIP2 HighHigh Not FoundNot Found Q8IWL2-2Q8IWL2-2 Isoform 2 of Pulmonary surfactant-associated protein A1Isoform 2 of Pulmonary surfactant-associated protein A1 SFTPA1SFTPA1 HighHigh Not FoundNot Found P40855P40855 Peroxisomal biogenesis factor 19Peroxisomal biogenesis factor 19 PEX19PEX19 HighHigh Not FoundNot Found Q92922Q92922 SWI/SNF complex subunit SMARCC1SWI/SNF complex subunit SMARCC1 SMARCC1SMARCC1 HighHigh Not FoundNot Found Q96QR1Q96QR1 Secretoglobin family 3A member 1Secretoglobin family 3A member 1 SCGB3A1SCGB3A1 HighHigh Not FoundNot Found P05413P05413 Fatty acid-binding protein, heartFatty acid-binding protein, heart FABP3FABP3 HighHigh Not FoundNot Found P51151P51151 Ras-related protein Rab-9ARas-related protein Rab-9A RAB9ARAB9A HighHigh Not FoundNot Found Q9BZF9Q9BZF9 Uveal autoantigen with coiled-coil domains and ankyrin repeatsUveal autoantigen with coiled-coil domains and ankyrin repeats UACAUACA HighHigh Not FoundNot Found Q8N5J2-3Q8N5J2-3 Isoform 3 of Ubiquitin carboxyl-terminal hydrolase MINDY-1Isoform 3 of Ubiquitin carboxyl-terminal hydrolase MINDY-1 MINDY1MINDY1 HighHigh Not FoundNot Found P49006P49006 MARCKS-related proteinMARCKS-related protein MARCKSL1MARCKSL1 HighHigh Not FoundNot Found A0A0C4DH31A0A0C4DH31 Immunoglobulin heavy variable 1-18Immunoglobulin heavy variable 1-18 IGHV1-18IGHV1-18 HighHigh Not FoundNot Found O00142-6O00142-6 Isoform 6 of Thymidine kinase 2, mitochondrialIsoform 6 of Thymidine kinase 2, mitochondrial TK2TK2 HighHigh Not FoundNot Found Q9BRF8Q9BRF8 Serine/threonine-protein phosphatase CPPED1Serine/threonine-protein phosphatase CPPED1 CPPED1CPPED1 HighHigh Not FoundNot Found Q96A49Q96A49 Synapse-associated protein 1Synapse-associated protein 1 SYAP1SYAP1 HighHigh Not FoundNot Found O43924O43924 Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit deltaRetinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta PDE6DPDE6D HighHigh Not FoundNot Found Q6I9Y2Q6I9Y2 THO complex subunit 7 homologTHO complex subunit 7 homolog THOC7THOC7 HighHigh Not FoundNot Found Q96SM3Q96SM3 Probable carboxypeptidase X1Probable carboxypeptidase X1 CPXM1CPXM1 HighHigh Not FoundNot Found Q86Y56Q86Y56 Dynein assembly factor 5, axonemalDynein assembly factor 5, axonemal DNAAF5DNAAF5 HighHigh Not FoundNot Found Q8NBK3Q8NBK3 Sulfatase-modifying factor 1Sulfatase-modifying factor 1 SUMF1SUMF1 HighHigh Not FoundNot Found P23588P23588 Eukaryotic translation initiation factor 4BEukaryotic translation initiation factor 4B EIF4BEIF4B HighHigh Not FoundNot Found Q13464Q13464 Rho-associated protein kinase 1Rho-associated protein kinase 1 ROCK1ROCK1 HighHigh Not FoundNot Found O15355O15355 Protein phosphatase 1GProtein phosphatase 1G PPM1GPPM1G HighHigh Not FoundNot Found P07204P07204 ThrombomodulinThrombomodulin THBDTHBD HighHigh Not FoundNot Found Q6P4F2Q6P4F2 Ferredoxin-2, mitochondrialFerredoxin-2, mitochondrial FDX2FDX2 HighHigh Not FoundNot Found P07998P07998 Ribonuclease pancreaticRibonuclease pancreatic RNASE1RNASE1 HighHigh Not FoundNot Found Q96A19Q96A19 Coiled-coil domain-containing protein 102ACoiled-coil domain-containing protein 102A CCDC102ACCDC102A HighHigh Not FoundNot Found O60687O60687 Sushi repeat-containing protein SRPX2Sushi repeat-containing protein SRPX2 SRPX2SRPX2 HighHigh Not FoundNot Found Q96IG2Q96IG2 F-box/LRR-repeat protein 20F-box/LRR-repeat protein 20 FBXL20FBXL20 HighHigh Not FoundNot Found Q9BWU0Q9BWU0 KanadaptinKanadaptin SLC4A1APSLC4A1AP HighHigh Not FoundNot Found Q9H1Z4Q9H1Z4 WD repeat-containing protein 13WD repeat-containing protein 13 WDR13WDR13 HighHigh Not FoundNot Found Q9Y3A3Q9Y3A3 MOB-like protein phoceinMOB-like protein phocein MOB4MOB4 HighHigh Not FoundNot Found Q9HCU0Q9HCU0 EndosialinEndosialin CD248CD248 HighHigh Not FoundNot Found Q14247-2Q14247-2 Isoform 2 of Src substrate cortactinIsoform 2 of Src substrate cortactin CTTNCTTN HighHigh Not FoundNot Found Q32P44-2Q32P44-2 Isoform 2 of Echinoderm microtubule-associated protein-like 3Isoform 2 of Echinoderm microtubule-associated protein-like 3 EML3EML3 HighHigh Not FoundNot Found P35658-5P35658-5 Isoform 5 of Nuclear pore complex protein Nup214Isoform 5 of Nuclear pore complex protein Nup214 NUP214NUP214 HighHigh Not FoundNot Found P53367P53367 Arfaptin-1Arfaptin-1 ARFIP1ARFIP1 HighHigh Not FoundNot Found O14964O14964 Hepatocyte growth factor-regulated tyrosine kinase substrateHepatocyte growth factor-regulated tyrosine kinase substrate HGSHGS HighHigh Not FoundNot Found Q9UGR2Q9UGR2 Zinc finger CCCH domain-containing protein 7BZinc finger CCCH domain-containing protein 7B ZC3H7BZC3H7B HighHigh Not FoundNot Found O14974O14974 Protein phosphatase 1 regulatory subunit 12AProtein phosphatase 1 regulatory subunit 12A PPP1R12APPP1R12A HighHigh Not FoundNot Found P61601P61601 Neurocalcin-deltaNeurocalcin-delta NCALDNCALD HighHigh Not FoundNot Found Q86SZ2Q86SZ2 Trafficking protein particle complex subunit 6BTrafficking protein particle complex subunit 6B TRAPPC6BTRAPPC6B HighHigh Not FoundNot Found Q9BX67Q9BX67 Junctional adhesion molecule CJunctional adhesion molecule C JAM3JAM3 HighHigh Not FoundNot Found Q8TB96Q8TB96 T-cell immunomodulatory proteinT-cell immunomodulatory protein ITFG1ITFG1 HighHigh Not FoundNot Found Q86YB8Q86YB8 ERO1-like protein betaERO1-like protein beta ERO1BERO1B HighHigh Not FoundNot Found Q86VS8Q86VS8 Protein Hook homolog 3Protein Hook homolog 3 HOOK3HOOK3 HighHigh Not FoundNot Found Q96T51Q96T51 RUN and FYVE domain-containing protein 1RUN and FYVE domain-containing protein 1 RUFY1RUFY1 HighHigh Not FoundNot Found Q14192Q14192 Four and a half LIM domains protein 2Four and a half LIM domains protein 2 FHL2FHL2 HighHigh Not FoundNot Found P60983P60983 Glia maturation factor betaGlia maturation factor beta GMFBGMFB HighHigh Not FoundNot Found O75063O75063 Glycosaminoglycan xylosylkinaseGlycosaminoglycan xylosylkinase FAM20BFAM20B HighHigh Not FoundNot Found P82094-2P82094-2 Isoform 2 of TATA element modulatory factorIsoform 2 of TATA element modulatory factor TMF1TMF1 HighHigh Not FoundNot Found O60784-2O60784-2 Isoform 2 of Target of Myb protein 1Isoform 2 of Target of Myb protein 1 TOM1TOM1 HighHigh Not FoundNot Found Q9H4A5Q9H4A5 Golgi phosphoprotein 3-likeGolgi phosphoprotein 3-like GOLPH3LGOLPH3L HighHigh Not FoundNot Found Q9NRN5Q9NRN5 Olfactomedin-like protein 3Olfactomedin-like protein 3 OLFML3OLFML3 HighHigh Not FoundNot Found Q9H2P0Q9H2P0 Activity-dependent neuroprotector homeobox proteinActivity-dependent neuroprotector homeobox protein ADNPADNP HighHigh Not FoundNot Found Q9NUM4Q9NUM4 Transmembrane protein 106BTransmembrane protein 106B TMEM106BTMEM106B HighHigh Not FoundNot Found Q8TDD1-2Q8TDD1-2 Isoform 2 of ATP-dependent RNA helicase DDX54Isoform 2 of ATP-dependent RNA helicase DDX54 DDX54DDX54 HighHigh Not FoundNot Found Q9NZ43Q9NZ43 Vesicle transport protein USE1Vesicle transport protein USE1 USE1USE1 HighHigh Not FoundNot Found P25940P25940 Collagen alpha-3(V) chainCollagen alpha-3(V) chain COL5A3COL5A3 HighHigh Not FoundNot Found Q9NVM1Q9NVM1 Protein eva-1 homolog BProtein eva-1 homolog B EVA1BEVA1B HighHigh Not FoundNot Found P49407P49407 Beta-arrestin-1Beta-arrestin-1 ARRB1ARRB1 HighHigh Not FoundNot Found Q9HD15Q9HD15 Steroid receptor RNA activator 1Steroid receptor RNA activator 1 SRA1SRA1 HighHigh Not FoundNot Found P30566P30566 Adenylosuccinate lyaseAdenylosuccinate lyase ADSLADSL HighHigh Not FoundNot Found Q9NPF4Q9NPF4 Probable tRNA N6-adenosine threonylcarbamoyltransferaseProbable tRNA N6-adenosine threonylcarbamoyltransferase OSGEPOSGEP HighHigh Not FoundNot Found P49902P49902 Cytosolic purine 5'-nucleotidaseCytosolic purine 5'-nucleotidase NT5C2NT5C2 HighHigh Not FoundNot Found Q4U2R6Q4U2R6 39S ribosomal protein L51, mitochondrial39S ribosomal protein L51, mitochondrial MRPL51MRPL51 HighHigh Not FoundNot Found Q99962Q99962 Endophilin-A1Endophilin-A1 SH3GL2SH3GL2 HighHigh Not FoundNot Found Q9UPT5-4Q9UPT5-4 Isoform 4 of Exocyst complex component 7Isoform 4 of Exocyst complex component 7 EXOC7EXOC7 HighHigh Not FoundNot Found O00757O00757 Fructose-1,6-bisphosphatase isozyme 2Fructose-1,6-bisphosphatase isozyme 2 FBP2FBP2 HighHigh Not FoundNot Found Q9UJA9Q9UJA9 Ectonucleotide pyrophosphatase/phosphodiesterase family member 5Ectonucleotide pyrophosphatase/phosphodiesterase family member 5 ENPP5ENPP5 HighHigh Not FoundNot Found Q9H1X3-3Q9H1X3-3 Isoform 3 of DnaJ homolog subfamily C member 25Isoform 3 of DnaJ homolog subfamily C member 25 DNAJC25DNAJC25 HighHigh Not FoundNot Found Q86U44Q86U44 N6-adenosine-methyltransferase 70 kDa subunitN6-adenosine-methyltransferase 70 kDa subunit METTL3METTL3 HighHigh Not FoundNot Found Q96SU4-6Q96SU4-6 Isoform 6 of Oxysterol-binding protein-related protein 9Isoform 6 of Oxysterol-binding protein-related protein 9 OSBPL9OSBPL9 HighHigh Not FoundNot Found Q8N201Q8N201 Integrator complex subunit 1Integrator complex subunit 1 INTS1INTS1 HighHigh Not FoundNot Found P61077-3P61077-3 Isoform 3 of Ubiquitin-conjugating enzyme E2 D3Isoform 3 of Ubiquitin-conjugating enzyme E2 D3 UBE2D3UBE2D3 HighHigh Not FoundNot Found O96014O96014 Protein Wnt-11Protein Wnt-11 WNT11WNT11 HighHigh Not FoundNot Found Q9Y6W3Q9Y6W3 Calpain-7Calpain-7 CAPN7CAPN7 HighHigh Not FoundNot Found P08582P08582 MelanotransferrinMelanotransferrin MELTFMELTF HighHigh Not FoundNot Found Q9NRF8Q9NRF8 CTP synthase 2CTP synthase 2 CTPS2CTPS2 HighHigh Not FoundNot Found Q13613Q13613 Myotubularin-related protein 1Myotubularin-related protein 1 MTMR1MTMR1 HighHigh Not FoundNot Found A0MZ66-3A0MZ66-3 Isoform 3 of Shootin-1Isoform 3 of Shootin-1 SHTN1SHTN1 HighHigh Not FoundNot Found Q9P2M7Q9P2M7 CingulinCingulin CGNCGN HighHigh Not FoundNot Found Q9UBW8Q9UBW8 COP9 signalosome complex subunit 7aCOP9 signalosome complex subunit 7a COPS7ACOPS7A HighHigh Not FoundNot Found O75716O75716 Serine/threonine-protein kinase 16Serine/threonine-protein kinase 16 STK16STK16 HighHigh Not FoundNot Found Q5EBL8-2Q5EBL8-2 Isoform 2 of PDZ domain-containing protein 11Isoform 2 of PDZ domain-containing protein 11 PDZD11PDZD11 HighHigh Not FoundNot Found Q9NS00Q9NS00 Glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1Glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1 C1GALT1C1GALT1 HighHigh Not FoundNot Found Q9H2U1Q9H2U1 ATP-dependent RNA helicase DHX36ATP-dependent RNA helicase DHX36 DHX36DHX36 HighHigh Not FoundNot Found Q9BZV1Q9BZV1 UBX domain-containing protein 6UBX domain-containing protein 6 UBXN6UBXN6 HighHigh Not FoundNot Found O94880O94880 PHD finger protein 14PHD finger protein 14 PHF14PHF14 HighHigh Not FoundNot Found Q96C19Q96C19 EF-hand domain-containing protein D2EF-hand domain-containing protein D2 EFHD2EFHD2 HighHigh Not FoundNot Found Q9Y5K5Q9Y5K5 Ubiquitin carboxyl-terminal hydrolase isozyme L5Ubiquitin carboxyl-terminal hydrolase isozyme L5 UCHL5UCHL5 HighHigh Not FoundNot Found O94911-3O94911-3 Isoform 3 of ATP-binding cassette sub-family A member 8Isoform 3 of ATP-binding cassette sub-family A member 8 ABCA8ABCA8 HighHigh Not FoundNot Found Q96LT9Q96LT9 RNA-binding protein 40RNA-binding protein 40 RNPC3RNPC3 HighHigh Not FoundNot Found O75152O75152 Zinc finger CCCH domain-containing protein 11AZinc finger CCCH domain-containing protein 11A ZC3H11AZC3H11A HighHigh Not FoundNot Found Q8N5I4Q8N5I4 Dehydrogenase/reductase SDR family member on chromosome XDehydrogenase/reductase SDR family member on chromosome X DHRSXDHRSX HighHigh Not FoundNot Found P23443P23443 Ribosomal protein S6 kinase beta-1Ribosomal protein S6 kinase beta-1 RPS6KB1RPS6KB1 HighHigh Not FoundNot Found Q6VY07-2Q6VY07-2 Isoform 2 of Phosphofurin acidic cluster sorting protein 1Isoform 2 of Phosphofurin acidic cluster sorting protein 1 PACS1PACS1 HighHigh Not FoundNot Found O14772O14772 Fucose-1-phosphate guanylyltransferaseFucose-1-phosphate guanylyltransferase FPGTFPGT HighHigh Not FoundNot Found Q96N67Q96N67 Dedicator of cytokinesis protein 7Dedicator of cytokinesis protein 7 DOCK7DOCK7 HighHigh Not FoundNot Found P03950P03950 AngiogeninAngiogenin ANGANG HighHigh Not FoundNot Found Q7Z5Y6Q7Z5Y6 Bone morphogenetic protein 8ABone morphogenetic protein 8A BMP8ABMP8A HighHigh Not FoundNot Found P54922P54922 [Protein ADP-ribosylarginine] hydrolase[Protein ADP-ribosylarginine] hydrolase ADPRHADPRH HighHigh Not FoundNot Found Q8IZA0Q8IZA0 Dyslexia-associated protein KIAA0319-like proteinDyslexia-associated protein KIAA0319-like protein KIAA0319LKIAA0319L HighHigh Not FoundNot Found Q6IC98Q6IC98 GRAM domain-containing protein 4GRAM domain-containing protein 4 GRAMD4GRAMD4 HighHigh Not FoundNot Found O00559-2O00559-2 Isoform 2 of Receptor-binding cancer antigen expressed on SiSo cellsIsoform 2 of Receptor-binding cancer antigen expressed on SiSo cells EBAG9EBAG9 HighHigh Not FoundNot Found Q9HAS0Q9HAS0 Protein Njmu-R1Protein Njmu-R1 C17orf75C17orf75 HighHigh Not FoundNot Found Q99567Q99567 Nuclear pore complex protein Nup88Nuclear pore complex protein Nup88 NUP88NUP88 HighHigh Not FoundNot Found Q05397-5Q05397-5 Isoform 5 of Focal adhesion kinase 1Isoform 5 of Focal adhesion kinase 1 PTK2PTK2 HighHigh Not FoundNot Found Q15654Q15654 Thyroid receptor-interacting protein 6Thyroid receptor-interacting protein 6 TRIP6TRIP6 HighHigh Not FoundNot Found O14562O14562 Ubiquitin domain-containing protein UBFD1Ubiquitin domain-containing protein UBFD1 UBFD1UBFD1 HighHigh Not FoundNot Found Q9BXW6Q9BXW6 Oxysterol-binding protein-related protein 1Oxysterol-binding protein-related protein 1 OSBPL1AOSBPL1A HighHigh Not FoundNot Found Q9P2I0Q9P2I0 Cleavage and polyadenylation specificity factor subunit 2Cleavage and polyadenylation specificity factor subunit 2 CPSF2CPSF2 HighHigh Not FoundNot Found Q5VSL9Q5VSL9 Striatin-interacting protein 1Striatin-interacting protein 1 STRIP1STRIP1 HighHigh Not FoundNot Found Q9P0U4-2Q9P0U4-2 Isoform 2 of CXXC-type zinc finger protein 1Isoform 2 of CXXC-type zinc finger protein 1 CXXC1CXXC1 HighHigh Not FoundNot Found Q969R5Q969R5 Lethal(3)malignant brain tumor-like protein 2Lethal(3)malignant brain tumor-like protein 2 L3MBTL2L3MBTL2 HighHigh Not FoundNot Found Q12926Q12926 ELAV-like protein 2ELAV-like protein 2 ELAVL2ELAVL2 HighHigh Not FoundNot Found P20908P20908 Collagen alpha-1(V) chainCollagen alpha-1(V) chain COL5A1COL5A1 HighHigh Not FoundNot Found Q9Y6F6-7Q9Y6F6-7 Isoform 7 of Protein MRVI1Isoform 7 of Protein MRVI1 MRVI1MRVI1 HighHigh Not FoundNot Found Q8NGA1Q8NGA1 Olfactory receptor 1M1Olfactory receptor 1M1 OR1M1OR1M1 HighHigh Not FoundNot Found Q96S66Q96S66 Chloride channel CLIC-like protein 1Chloride channel CLIC-like protein 1 CLCC1CLCC1 HighHigh Not FoundNot Found Q9P2P5Q9P2P5 E3 ubiquitin-protein ligase HECW2E3 ubiquitin-protein ligase HECW2 HECW2HECW2 HighHigh Not FoundNot Found O43592O43592 Exportin-TExportin-T XPOTXPOT HighHigh Not FoundNot Found Q9H0R8-2Q9H0R8-2 Isoform 2 of Gamma-aminobutyric acid receptor-associated protein-like 1Isoform 2 of Gamma-aminobutyric acid receptor-associated protein-like 1 GABARAPL1GABARAPL1 HighHigh Not FoundNot Found O43290O43290 U4/U6.U5 tri-snRNP-associated protein 1U4/U6.U5 tri-snRNP-associated protein 1 SART1SART1 HighHigh Not FoundNot Found Q86U86Q86U86 Protein polybromo-1Protein polybromo-1 PBRM1PBRM1 HighHigh Not FoundNot Found Q14728Q14728 Major facilitator superfamily domain-containing protein 10Major facilitator superfamily domain-containing protein 10 MFSD10MFSD10 HighHigh Not FoundNot Found P49914P49914 5-formyltetrahydrofolate cyclo-ligase5-formyltetrahydrofolate cyclo-ligase MTHFSMTHFS HighHigh Not FoundNot Found Q68CP9Q68CP9 AT-rich interactive domain-containing protein 2AT-rich interactive domain-containing protein 2 ARID2ARID2 HighHigh Not FoundNot Found Q8NCK7Q8NCK7 Monocarboxylate transporter 11Monocarboxylate transporter 11 SLC16A11SLC16A11 HighHigh Not FoundNot Found P48745P48745 Protein NOV homologProtein NOV homolog NOVNOV HighHigh Not FoundNot Found P06746P06746 DNA polymerase betaDNA polymerase beta POLBPOLB HighHigh Not FoundNot Found O43847-2O43847-2 Isoform 2 of NardilysinIsoform 2 of Nardilysin NRDCNRDC HighHigh Not FoundNot Found Q9Y385Q9Y385 Ubiquitin-conjugating enzyme E2 J1Ubiquitin-conjugating enzyme E2 J1 UBE2J1UBE2J1 HighHigh Not FoundNot Found Q96AA8-3Q96AA8-3 Isoform 3 of Janus kinase and microtubule-interacting protein 2Isoform 3 of Janus kinase and microtubule-interacting protein 2 JAKMIP2JAKMIP2 HighHigh Not FoundNot Found P98173P98173 Protein FAM3AProtein FAM3A FAM3AFAM3A HighHigh Not FoundNot Found P54278P54278 Mismatch repair endonuclease PMS2Mismatch repair endonuclease PMS2 PMS2PMS2 HighHigh Not FoundNot Found Q9Y6Q3-2Q9Y6Q3-2 Isoform 2 of Zinc finger protein 37 homologIsoform 2 of Zinc finger protein 37 homolog ZFP37ZFP37 HighHigh Not FoundNot Found Q8N465Q8N465 D-2-hydroxyglutarate dehydrogenase, mitochondrialD-2-hydroxyglutarate dehydrogenase, mitochondrial D2HGDHD2HGDH HighHigh Not FoundNot Found Q15413Q15413 Ryanodine receptor 3Ryanodine receptor 3 RYR3RYR3 HighHigh Not FoundNot Found P46821P46821 Microtubule-associated protein 1BMicrotubule-associated protein 1B MAP1BMAP1B HighHigh Not FoundNot Found Q86UV5-8Q86UV5-8 Isoform 8 of Ubiquitin carboxyl-terminal hydrolase 48Isoform 8 of Ubiquitin carboxyl-terminal hydrolase 48 USP48USP48 HighHigh Not FoundNot Found Q6YHK3Q6YHK3 CD109 antigenCD109 antigen CD109CD109 HighHigh Not FoundNot Found O95182O95182 NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 NDUFA7NDUFA7 HighHigh Not FoundNot Found Q96BR1Q96BR1 Serine/threonine-protein kinase Sgk3Serine/threonine-protein kinase Sgk3 SGK3SGK3 HighHigh Not FoundNot Found Q9BRC7Q9BRC7 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-41-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 PLCD4PLCD4 HighHigh Not FoundNot Found Q05048Q05048 Cleavage stimulation factor subunit 1Cleavage stimulation factor subunit 1 CSTF1CSTF1 HighHigh Not FoundNot Found O43670-4O43670-4 Isoform 4 of BUB3-interacting and GLEBS motif-containing protein ZNF207Isoform 4 of BUB3-interacting and GLEBS motif-containing protein ZNF207 ZNF207ZNF207 HighHigh Not FoundNot Found Q13501Q13501 Sequestosome-1Sequestosome-1 SQSTM1SQSTM1 HighHigh Not FoundNot Found Q05086Q05086 Ubiquitin-protein ligase E3AUbiquitin-protein ligase E3A UBE3AUBE3A HighHigh Not FoundNot Found O95976O95976 Immunoglobulin superfamily member 6Immunoglobulin superfamily member 6 IGSF6IGSF6 HighHigh Not FoundNot Found P57764P57764 Gasdermin-DGasdermin-D GSDMDGSDMD HighHigh Not FoundNot Found O75223O75223 Gamma-glutamylcyclotransferaseGamma-glutamylcyclotransferase GGCTGGCT HighHigh Not FoundNot Found Q15025Q15025 TNFAIP3-interacting protein 1TNFAIP3-interacting protein 1 TNIP1TNIP1 HighHigh Not FoundNot Found Q9BXM0Q9BXM0 PeriaxinPeriaxin PRXPRX HighHigh Not FoundNot Found Q96PX9Q96PX9 Pleckstrin homology domain-containing family G member 4BPleckstrin homology domain-containing family G member 4B PLEKHG4BPLEKHG4B HighHigh Not FoundNot Found A2RTX5A2RTX5 Probable threonine--tRNA ligase 2, cytoplasmicProbable threonine--tRNA ligase 2, cytoplasmic TARSL2TARSL2 HighHigh Not FoundNot Found P52948P52948 Nuclear pore complex protein Nup98-Nup96Nuclear pore complex protein Nup98-Nup96 NUP98NUP98 HighHigh Not FoundNot Found Q09472Q09472 Histone acetyltransferase p300Histone acetyltransferase p300 EP300EP300 HighHigh Not FoundNot Found Q7Z3K3Q7Z3K3 Pogo transposable element with ZNF domainPogo transposable element with ZNF domain POGZPOGZ HighHigh Not FoundNot Found Q8WVQ1Q8WVQ1 Soluble calcium-activated nucleotidase 1Soluble calcium-activated nucleotidase 1 CANT1CANT1 HighHigh Not FoundNot Found P48454-3P48454-3 Isoform 3 of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoformIsoform 3 of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform PPP3CCPPP3CC HighHigh Not FoundNot Found Q13367-4Q13367-4 Isoform 4 of AP-3 complex subunit beta-2Isoform 4 of AP-3 complex subunit beta-2 AP3B2AP3B2 HighHigh Not FoundNot Found Q13114-2Q13114-2 Isoform 2 of TNF receptor-associated factor 3Isoform 2 of TNF receptor-associated factor 3 TRAF3TRAF3 HighHigh Not FoundNot Found Q96JE7Q96JE7 Protein transport protein Sec16BProtein transport protein Sec16B SEC16BSEC16B HighHigh Not FoundNot Found P33240P33240 Cleavage stimulation factor subunit 2Cleavage stimulation factor subunit 2 CSTF2CSTF2 HighHigh Not FoundNot Found Q8N967Q8N967 Leucine-rich repeat and transmembrane domain-containing protein 2Leucine-rich repeat and transmembrane domain-containing protein 2 LRTM2LRTM2 HighHigh Not FoundNot Found Q14667Q14667 Protein KIAA0100Protein KIAA0100 KIAA0100KIAA0100 HighHigh Not FoundNot Found Q8IZU8Q8IZU8 Dermatan-sulfate epimerase-like proteinDermatan-sulfate epimerase-like protein DSELDSEL HighHigh Not FoundNot Found

NIFTP에서만 동정되고 침윤성 EFVPTC에서는 검출되지 않은 단백질Protein identified only in NIFTP and not detected in invasive EFVPTC InformationInformation Found in Sample GroupFound in Sample Group AccessionAccession ProteinNameProteinName GeneNameGeneName EFVPTCEFVPTC NIFTPNIFTP P30486P30486 HLA class I histocompatibility antigen, B-48 alpha chainHLA class I histocompatibility antigen, B-48 alpha chain HLA-BHLA-B Not FoundNot Found HighHigh Q2TB90Q2TB90 Putative hexokinase HKDC1Putative hexokinase HKDC1 HKDC1HKDC1 Not FoundNot Found HighHigh P78386P78386 Keratin, type II cuticular Hb5Keratin, type II cuticular Hb5 KRT85KRT85 Not FoundNot Found HighHigh P13747P13747 HLA class I histocompatibility antigen, alpha chain EHLA class I histocompatibility antigen, alpha chain E HLA-EHLA-E Not FoundNot Found HighHigh Q96HN2Q96HN2 Adenosylhomocysteinase 3Adenosylhomocysteinase 3 AHCYL2AHCYL2 Not FoundNot Found HighHigh Q8TDQ7Q8TDQ7 Glucosamine-6-phosphate isomerase 2Glucosamine-6-phosphate isomerase 2 GNPDA2GNPDA2 Not FoundNot Found HighHigh O75828O75828 Carbonyl reductase [NADPH] 3Carbonyl reductase [NADPH] 3 CBR3CBR3 Not FoundNot Found HighHigh P11908-2P11908-2 Isoform 2 of Ribose-phosphate pyrophosphokinase 2Isoform 2 of Ribose-phosphate pyrophosphokinase 2 PRPS2PRPS2 Not FoundNot Found HighHigh Q9NRK6Q9NRK6 ATP-binding cassette sub-family B member 10, mitochondrialATP-binding cassette sub-family B member 10, mitochondrial ABCB10ABCB10 Not FoundNot Found HighHigh Q9NSB2Q9NSB2 Keratin, type II cuticular Hb4Keratin, type II cuticular Hb4 KRT84KRT84 Not FoundNot Found HighHigh O95837O95837 Guanine nucleotide-binding protein subunit alpha-14Guanine nucleotide-binding protein subunit alpha-14 GNA14GNA14 Not FoundNot Found HighHigh Q14525Q14525 Keratin, type I cuticular Ha3-IIKeratin, type I cuticular Ha3-II KRT33BKRT33B Not FoundNot Found HighHigh A6NE02A6NE02 BTB/POZ domain-containing protein 17BTB/POZ domain-containing protein 17 BTBD17BTBD17 Not FoundNot Found HighHigh P83110P83110 Serine protease HTRA3Serine protease HTRA3 HTRA3HTRA3 Not FoundNot Found HighHigh P13612P13612 Integrin alpha-4Integrin alpha-4 ITGA4ITGA4 Not FoundNot Found HighHigh O60907O60907 F-box-like/WD repeat-containing protein TBL1XF-box-like/WD repeat-containing protein TBL1X TBL1XTBL1X Not FoundNot Found HighHigh Q9NX05Q9NX05 Constitutive coactivator of PPAR-gamma-like protein 2Constitutive coactivator of PPAR-gamma-like protein 2 FAM120CFAM120C Not FoundNot Found HighHigh Q92629-2Q92629-2 Isoform 2 of Delta-sarcoglycanIsoform 2 of Delta-sarcoglycan SGCDSGCD Not FoundNot Found HighHigh P33241-3P33241-3 Isoform 3 of Lymphocyte-specific protein 1Isoform 3 of Lymphocyte-specific protein 1 LSP1LSP1 Not FoundNot Found HighHigh Q12788Q12788 Transducin beta-like protein 3Transducin beta-like protein 3 TBL3TBL3 Not FoundNot Found HighHigh Q8N4Q1-2Q8N4Q1-2 Isoform 2 of Mitochondrial intermembrane space import and assembly protein 40Isoform 2 of Mitochondrial intermembrane space import and assembly protein 40 CHCHD4CHCHD4 Not FoundNot Found HighHigh Q9BUB7Q9BUB7 Transmembrane protein 70, mitochondrialTransmembrane protein 70, mitochondrial TMEM70TMEM70 Not FoundNot Found HighHigh Q8N4Q0Q8N4Q0 Prostaglandin reductase 3Prostaglandin reductase 3 ZADH2ZADH2 Not FoundNot Found HighHigh Q8IWT6Q8IWT6 Volume-regulated anion channel subunit LRRC8AVolume-regulated anion channel subunit LRRC8A LRRC8ALRRC8A Not FoundNot Found HighHigh Q6ZUX7Q6ZUX7 Lipoma HMGIC fusion partner-like 2 proteinLipoma HMGIC fusion partner-like 2 protein LHFPL2LHFPL2 Not FoundNot Found HighHigh Q9NRA1Q9NRA1 Platelet-derived growth factor CPlatelet-derived growth factor C PDGFCPDGFC Not FoundNot Found HighHigh Q5SRE5Q5SRE5 Nucleoporin NUP188 homologNucleoporin NUP188 homolog NUP188NUP188 Not FoundNot Found HighHigh P00742P00742 Coagulation factor XCoagulation factor X F10F10 Not FoundNot Found HighHigh Q9NVZ3-2Q9NVZ3-2 Isoform 2 of Adaptin ear-binding coat-associated protein 2Isoform 2 of Adaptin ear-binding coat-associated protein 2 NECAP2NECAP2 Not FoundNot Found HighHigh Q8IYJ3Q8IYJ3 Synaptotagmin-like protein 1Synaptotagmin-like protein 1 SYTL1SYTL1 Not FoundNot Found HighHigh Q15382Q15382 GTP-binding protein RhebGTP-binding protein Rheb RHEBRHEB Not FoundNot Found HighHigh P62841P62841 40S ribosomal protein S1540S ribosomal protein S15 RPS15RPS15 Not FoundNot Found HighHigh O00178O00178 GTP-binding protein 1GTP-binding protein 1 GTPBP1GTPBP1 Not FoundNot Found HighHigh Q8IWA4Q8IWA4 Mitofusin-1Mitofusin-1 MFN1MFN1 Not FoundNot Found HighHigh P08246P08246 Neutrophil elastaseNeutrophil elastase ELANEELANE Not FoundNot Found HighHigh Q6ZRI8Q6ZRI8 Rho GTPase-activating protein 36Rho GTPase-activating protein 36 ARHGAP36ARHGAP36 Not FoundNot Found HighHigh Q68D85Q68D85 Natural cytotoxicity triggering receptor 3 ligand 1Natural cytotoxicity triggering receptor 3 ligand 1 NCR3LG1NCR3LG1 Not FoundNot Found HighHigh Q07092Q07092 Collagen alpha-1(XVI) chainCollagen alpha-1(XVI) chain COL16A1COL16A1 Not FoundNot Found HighHigh O94804O94804 Serine/threonine-protein kinase 10Serine/threonine-protein kinase 10 STK10STK10 Not FoundNot Found HighHigh Q9NVR2Q9NVR2 Integrator complex subunit 10Integrator complex subunit 10 INTS10INTS10 Not FoundNot Found HighHigh Q14694-2Q14694-2 Isoform 2 of Ubiquitin carboxyl-terminal hydrolase 10Isoform 2 of Ubiquitin carboxyl-terminal hydrolase 10 USP10USP10 Not FoundNot Found HighHigh Q92609-2Q92609-2 Isoform 2 of TBC1 domain family member 5Isoform 2 of TBC1 domain family member 5 TBC1D5TBC1D5 Not FoundNot Found HighHigh Q9NQL2Q9NQL2 Ras-related GTP-binding protein DRas-related GTP-binding protein D RRAGDRRAGD Not FoundNot Found HighHigh Q3MHD2-2Q3MHD2-2 Isoform 2 of Protein LSM12 homologIsoform 2 of Protein LSM12 homolog LSM12LSM12 Not FoundNot Found HighHigh Q92673Q92673 Sortilin-related receptorSortilin-related receptor SORL1SORL1 Not FoundNot Found HighHigh P08493-2P08493-2 Isoform 2 of Matrix Gla proteinIsoform 2 of Matrix Gla protein MGPMGP Not FoundNot Found HighHigh Q8N4S9Q8N4S9 MARVEL domain-containing protein 2MARVEL domain-containing protein 2 MARVELD2MARVELD2 Not FoundNot Found HighHigh O76013O76013 Keratin, type I cuticular Ha6Keratin, type I cuticular Ha6 KRT36KRT36 Not FoundNot Found HighHigh P23458P23458 Tyrosine-protein kinase JAK1Tyrosine-protein kinase JAK1 JAK1JAK1 Not FoundNot Found HighHigh P06681P06681 Complement C2Complement C2 C2C2 Not FoundNot Found HighHigh P16444P16444 Dipeptidase 1Dipeptidase 1 DPEP1DPEP1 Not FoundNot Found HighHigh Q9NYP7-2Q9NYP7-2 Isoform 2 of Elongation of very long chain fatty acids protein 5Isoform 2 of Elongation of very long chain fatty acids protein 5 ELOVL5ELOVL5 Not FoundNot Found HighHigh Q13018Q13018 Secretory phospholipase A2 receptorSecretory phospholipase A2 receptor PLA2R1PLA2R1 Not FoundNot Found HighHigh Q99519Q99519 Sialidase-1Sialidase-1 NEU1NEU1 Not FoundNot Found HighHigh Q13951-2Q13951-2 Isoform 2 of Core-binding factor subunit betaIsoform 2 of Core-binding factor subunit beta CBFBCBFB Not FoundNot Found HighHigh Q9Y316-3Q9Y316-3 Isoform 3 of Protein MEMO1Isoform 3 of Protein MEMO1 MEMO1MEMO1 Not FoundNot Found HighHigh P49863P49863 Granzyme KGranzyme K GZMKGZMK Not FoundNot Found HighHigh Q5TGZ0Q5TGZ0 MICOS complex subunit MIC10MICOS complex subunit MIC10 MINOS1MINOS1 Not FoundNot Found HighHigh Q9HCE1Q9HCE1 Putative helicase MOV-10Putative helicase MOV-10 MOV10MOV10 Not FoundNot Found HighHigh Q14376Q14376 UDP-glucose 4-epimeraseUDP-glucose 4-epimerase GALEGALE Not FoundNot Found HighHigh Q4G0F5Q4G0F5 Vacuolar protein sorting-associated protein 26BVacuolar protein sorting-associated protein 26B VPS26BVPS26B Not FoundNot Found HighHigh Q9NPH3-5Q9NPH3-5 Isoform 4 of Interleukin-1 receptor accessory proteinIsoform 4 of Interleukin-1 receptor accessory protein IL1RAPIL1RAP Not FoundNot Found HighHigh Q8TEX9-2Q8TEX9-2 Isoform 2 of Importin-4Isoform 2 of Importin-4 IPO4IPO4 Not FoundNot Found HighHigh Q96GM5Q96GM5 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 SMARCD1SMARCD1 Not FoundNot Found HighHigh Q99712Q99712 ATP-sensitive inward rectifier potassium channel 15ATP-sensitive inward rectifier potassium channel 15 KCNJ15KCNJ15 Not FoundNot Found HighHigh O95436O95436 Sodium-dependent phosphate transport protein 2BSodium-dependent phosphate transport protein 2B SLC34A2SLC34A2 Not FoundNot Found HighHigh O75309O75309 Cadherin-16Cadherin-16 CDH16CDH16 Not FoundNot Found HighHigh Q13469Q13469 Nuclear factor of activated T-cells, cytoplasmic 2Nuclear factor of activated T-cells, cytoplasmic 2 NFATC2NFATC2 Not FoundNot Found HighHigh P38571P38571 Lysosomal acid lipase/cholesteryl ester hydrolaseLysosomal acid lipase/cholesteryl ester hydrolase LIPALIPA Not FoundNot Found HighHigh Q9H329Q9H329 Band 4.1-like protein 4BBand 4.1-like protein 4B EPB41L4BEPB41L4B Not FoundNot Found HighHigh O00622O00622 Protein CYR61Protein CYR61 CYR61CYR61 Not FoundNot Found HighHigh Q86UX7Q86UX7 Fermitin family homolog 3Fermitin family homolog 3 FERMT3FERMT3 Not FoundNot Found HighHigh Q15109-6Q15109-6 Isoform 6 of Advanced glycosylation end product-specific receptorIsoform 6 of Advanced glycosylation end product-specific receptor AGERAGER Not FoundNot Found HighHigh Q53HC9Q53HC9 Protein TSSC1Protein TSSC1 EIPR1EIPR1 Not FoundNot Found HighHigh Q96JH7Q96JH7 Deubiquitinating protein VCIP135Deubiquitinating protein VCIP135 VCPIP1VCPIP1 Not FoundNot Found HighHigh Q9UBB5Q9UBB5 Methyl-CpG-binding domain protein 2Methyl-CpG-binding domain protein 2 MBD2MBD2 Not FoundNot Found HighHigh Q8IZJ3Q8IZJ3 C3 and PZP-like alpha-2-macroglobulin domain-containing protein 8C3 and PZP-like alpha-2-macroglobulin domain-containing protein 8 CPAMD8CPAMD8 Not FoundNot Found HighHigh P15941-2P15941-2 Isoform 2 of Mucin-1Isoform 2 of Mucin-1 MUC1MUC1 Not FoundNot Found HighHigh Q9NWZ5Q9NWZ5 Uridine-cytidine kinase-like 1Uridine-cytidine kinase-like 1 UCKL1UCKL1 Not FoundNot Found HighHigh Q9BSJ2-4Q9BSJ2-4 Isoform 3 of Gamma-tubulin complex component 2Isoform 3 of Gamma-tubulin complex component 2 TUBGCP2TUBGCP2 Not FoundNot Found HighHigh Q12830Q12830 Nucleosome-remodeling factor subunit BPTFNucleosome-remodeling factor subunit BPTF BPTFBPTF Not FoundNot Found HighHigh Q15291Q15291 Retinoblastoma-binding protein 5Retinoblastoma-binding protein 5 RBBP5RBBP5 Not FoundNot Found HighHigh Q92541Q92541 RNA polymerase-associated protein RTF1 homologRNA polymerase-associated protein RTF1 homolog RTF1RTF1 Not FoundNot Found HighHigh Q9UER7Q9UER7 Death domain-associated protein 6Death domain-associated protein 6 DAXXDAXX Not FoundNot Found HighHigh P19387P19387 DNA-directed RNA polymerase II subunit RPB3DNA-directed RNA polymerase II subunit RPB3 POLR2CPOLR2C Not FoundNot Found HighHigh Q96RL7Q96RL7 Vacuolar protein sorting-associated protein 13AVacuolar protein sorting-associated protein 13A VPS13AVPS13A Not FoundNot Found HighHigh O15379-2O15379-2 Isoform 2 of Histone deacetylase 3Isoform 2 of Histone deacetylase 3 HDAC3HDAC3 Not FoundNot Found HighHigh O00154O00154 Cytosolic acyl coenzyme A thioester hydrolaseCytosolic acyl coenzyme A thioester hydrolase ACOT7ACOT7 Not FoundNot Found HighHigh Q9H871Q9H871 Protein RMD5 homolog AProtein RMD5 homolog A RMND5ARMND5A Not FoundNot Found HighHigh P20702P20702 Integrin alpha-XIntegrin alpha-X ITGAXITGAX Not FoundNot Found HighHigh P30520P30520 Adenylosuccinate synthetase isozyme 2Adenylosuccinate synthetase isozyme 2 ADSSADSS Not FoundNot Found HighHigh Q9BZH6Q9BZH6 WD repeat-containing protein 11WD repeat-containing protein 11 WDR11WDR11 Not FoundNot Found HighHigh Q96D05-2Q96D05-2 Isoform 2 of Uncharacterized protein C10orf35Isoform 2 of Uncharacterized protein C10orf35 C10orf35C10orf35 Not FoundNot Found HighHigh P78381-4P78381-4 Isoform 4 of UDP-galactose translocatorIsoform 4 of UDP-galactose translocator SLC35A2SLC35A2 Not FoundNot Found HighHigh Q9H6X2Q9H6X2 Anthrax toxin receptor 1Anthrax toxin receptor 1 ANTXR1ANTXR1 Not FoundNot Found HighHigh P28068P28068 HLA class II histocompatibility antigen, DM beta chainHLA class II histocompatibility antigen, DM beta chain HLA-DMBHLA-DMB Not FoundNot Found HighHigh Q9H1B5Q9H1B5 Xylosyltransferase 2Xylosyltransferase 2 XYLT2XYLT2 Not FoundNot Found HighHigh Q9H788Q9H788 SH2 domain-containing protein 4ASH2 domain-containing protein 4A SH2D4ASH2D4A Not FoundNot Found HighHigh Q8N3V7Q8N3V7 SynaptopodinSynaptopodin SYNPOSYNPO Not FoundNot Found HighHigh Q9HC16Q9HC16 DNA dC->dU-editing enzyme APOBEC-3GDNA dC->dU-editing enzyme APOBEC-3G APOBEC3GAPOBEC3G Not FoundNot Found HighHigh P62068P62068 Ubiquitin carboxyl-terminal hydrolase 46Ubiquitin carboxyl-terminal hydrolase 46 USP46USP46 Not FoundNot Found HighHigh Q9UQB8Q9UQB8 Brain-specific angiogenesis inhibitor 1-associated protein 2Brain-specific angiogenesis inhibitor 1-associated protein 2 BAIAP2BAIAP2 Not FoundNot Found HighHigh Q9NPA8Q9NPA8 Transcription and mRNA export factor ENY2Transcription and mRNA export factor ENY2 ENY2ENY2 Not FoundNot Found HighHigh Q15269Q15269 Periodic tryptophan protein 2 homologPeriodic tryptophan protein 2 homolog PWP2PWP2 Not FoundNot Found HighHigh O14976O14976 Cyclin-G-associated kinaseCyclin-G-associated kinase GAKGAK Not FoundNot Found HighHigh P29323P29323 Ephrin type-B receptor 2Ephrin type-B receptor 2 EPHB2EPHB2 Not FoundNot Found HighHigh Q9UQ52Q9UQ52 Contactin-6Contactin-6 CNTN6CNTN6 Not FoundNot Found HighHigh Q32P28-3Q32P28-3 Isoform 3 of Prolyl 3-hydroxylase 1Isoform 3 of Prolyl 3-hydroxylase 1 P3H1P3H1 Not FoundNot Found HighHigh Q9H7B4Q9H7B4 Histone-lysine N-methyltransferase SMYD3Histone-lysine N-methyltransferase SMYD3 SMYD3SMYD3 Not FoundNot Found HighHigh Q8N1G2Q8N1G2 Cap-specific mRNA (nucleoside-2'-O-)-methyltransferase 1Cap-specific mRNA (nucleoside-2'-O-)-methyltransferase 1 CMTR1CMTR1 Not FoundNot Found HighHigh P08138P08138 Tumor necrosis factor receptor superfamily member 16Tumor necrosis factor receptor superfamily member 16 NGFRNGFR Not FoundNot Found HighHigh O75094-4O75094-4 Isoform 4 of Slit homolog 3 proteinIsoform 4 of Slit homolog 3 protein SLIT3SLIT3 Not FoundNot Found HighHigh Q96F10Q96F10 Diamine acetyltransferase 2Diamine acetyltransferase 2 SAT2SAT2 Not FoundNot Found HighHigh Q7LFX5Q7LFX5 Carbohydrate sulfotransferase 15Carbohydrate sulfotransferase 15 CHST15CHST15 Not FoundNot Found HighHigh Q5VT52Q5VT52 Regulation of nuclear pre-mRNA domain-containing protein 2Regulation of nuclear pre-mRNA domain-containing protein 2 RPRD2RPRD2 Not FoundNot Found HighHigh Q7L1V2Q7L1V2 Vacuolar fusion protein MON1 homolog BVacuolar fusion protein MON1 homolog B MON1BMON1B Not FoundNot Found HighHigh O14975O14975 Very long-chain acyl-CoA synthetaseVery long-chain acyl-CoA synthetase SLC27A2SLC27A2 Not FoundNot Found HighHigh Q7Z412Q7Z412 Peroxisome assembly protein 26Peroxisome assembly protein 26 PEX26PEX26 Not FoundNot Found HighHigh O95251O95251 Histone acetyltransferase KAT7Histone acetyltransferase KAT7 KAT7KAT7 Not FoundNot Found HighHigh Q9BRP4Q9BRP4 Proteasomal ATPase-associated factor 1Proteasomal ATPase-associated factor 1 PAAF1PAAF1 Not FoundNot Found HighHigh P31994P31994 Low affinity immunoglobulin gamma Fc region receptor II-bLow affinity immunoglobulin gamma Fc region receptor II-b FCGR2BFCGR2B Not FoundNot Found HighHigh Q9ULU4-19Q9ULU4-19 Isoform 19 of Protein kinase C-binding protein 1Isoform 19 of Protein kinase C-binding protein 1 ZMYND8ZMYND8 Not FoundNot Found HighHigh Q13017Q13017 Rho GTPase-activating protein 5Rho GTPase-activating protein 5 ARHGAP5ARHGAP5 Not FoundNot Found HighHigh Q8N2H3Q8N2H3 Pyridine nucleotide-disulfide oxidoreductase domain-containing protein 2Pyridine nucleotide-disulfide oxidoreductase domain-containing protein 2 PYROXD2PYROXD2 Not FoundNot Found HighHigh O00338-2O00338-2 Isoform Long of Sulfotransferase 1C2Isoform Long of Sulfotransferase 1C2 SULT1C2SULT1C2 Not FoundNot Found HighHigh Q9UJV3Q9UJV3 Probable E3 ubiquitin-protein ligase MID2Probable E3 ubiquitin-protein ligase MID2 MID2MID2 Not FoundNot Found HighHigh Q9BZM4Q9BZM4 NKG2D ligand 3NKG2D ligand 3 ULBP3ULBP3 Not FoundNot Found HighHigh P30530P30530 Tyrosine-protein kinase receptor UFOTyrosine-protein kinase receptor UFO AXLAXL Not FoundNot Found HighHigh P01732-3P01732-3 Isoform 3 of T-cell surface glycoprotein CD8 alpha chainIsoform 3 of T-cell surface glycoprotein CD8 alpha chain CD8ACD8A Not FoundNot Found HighHigh Q9BV23Q9BV23 Monoacylglycerol lipase ABHD6Monoacylglycerol lipase ABHD6 ABHD6ABHD6 Not FoundNot Found HighHigh O95832O95832 Claudin-1Claudin-1 CLDN1CLDN1 Not FoundNot Found HighHigh Q13616Q13616 Cullin-1Cullin-1 CUL1CUL1 Not FoundNot Found HighHigh Q9NRX1Q9NRX1 RNA-binding protein PNO1RNA-binding protein PNO1 PNO1PNO1 Not FoundNot Found HighHigh Q95460Q95460 Major histocompatibility complex class I-related gene proteinMajor histocompatibility complex class I-related gene protein MR1MR1 Not FoundNot Found HighHigh P18440P18440 Arylamine N-acetyltransferase 1Arylamine N-acetyltransferase 1 NAT1NAT1 Not FoundNot Found HighHigh Q5VTL8Q5VTL8 Pre-mRNA-splicing factor 38BPre-mRNA-splicing factor 38B PRPF38BPRPF38B Not FoundNot Found HighHigh Q9NVH0Q9NVH0 Exonuclease 3'-5' domain-containing protein 2Exonuclease 3'-5' domain-containing protein 2 EXD2EXD2 Not FoundNot Found HighHigh O95258-3O95258-3 Isoform 3 of Brain mitochondrial carrier protein 1Isoform 3 of Brain mitochondrial carrier protein 1 SLC25A14SLC25A14 Not FoundNot Found HighHigh P52701P52701 DNA mismatch repair protein Msh6DNA mismatch repair protein Msh6 MSH6MSH6 Not FoundNot Found HighHigh Q9H0D2Q9H0D2 Zinc finger protein 541Zinc finger protein 541 ZNF541ZNF541 Not FoundNot Found HighHigh P41218P41218 Myeloid cell nuclear differentiation antigenMyeloid cell nuclear differentiation antigen MNDAMNDA Not FoundNot Found HighHigh Q9Y2G5Q9Y2G5 GDP-fucose protein O-fucosyltransferase 2GDP-fucose protein O-fucosyltransferase 2 POFUT2POFUT2 Not FoundNot Found HighHigh Q99797Q99797 Mitochondrial intermediate peptidaseMitochondrial intermediate peptidase MIPEPMIPEP Not FoundNot Found HighHigh Q8IWA0Q8IWA0 WD repeat-containing protein 75WD repeat-containing protein 75 WDR75WDR75 Not FoundNot Found HighHigh Q9NX52Q9NX52 Rhomboid-related protein 2Rhomboid-related protein 2 RHBDL2RHBDL2 Not FoundNot Found HighHigh Q13315Q13315 Serine-protein kinase ATMSerine-protein kinase ATM ATMATM Not FoundNot Found HighHigh Q5VTR2Q5VTR2 E3 ubiquitin-protein ligase BRE1AE3 ubiquitin-protein ligase BRE1A RNF20RNF20 Not FoundNot Found HighHigh Q9Y2I8-2Q9Y2I8-2 Isoform 2 of WD repeat-containing protein 37Isoform 2 of WD repeat-containing protein 37 WDR37WDR37 Not FoundNot Found HighHigh P19174-2P19174-2 Isoform 2 of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1Isoform 2 of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 PLCG1PLCG1 Not FoundNot Found HighHigh A4D1E9A4D1E9 GTP-binding protein 10GTP-binding protein 10 GTPBP10GTPBP10 Not FoundNot Found HighHigh Q8N3G9Q8N3G9 Transmembrane protein 130Transmembrane protein 130 TMEM130TMEM130 Not FoundNot Found HighHigh Q8IY67-2Q8IY67-2 Isoform 2 of Ribonucleoprotein PTB-binding 1Isoform 2 of Ribonucleoprotein PTB-binding 1 RAVER1RAVER1 Not FoundNot Found HighHigh Q9C0D5Q9C0D5 Protein TANC1Protein TANC1 TANC1TANC1 Not FoundNot Found HighHigh Q00403Q00403 Transcription initiation factor IIBTranscription initiation factor IIB GTF2BGTF2B Not FoundNot Found HighHigh O95625O95625 Zinc finger and BTB domain-containing protein 11Zinc finger and BTB domain-containing protein 11 ZBTB11ZBTB11 Not FoundNot Found HighHigh Q12767-2Q12767-2 Isoform 2 of Transmembrane protein 94Isoform 2 of Transmembrane protein 94 TMEM94TMEM94 Not FoundNot Found HighHigh Q96ST3Q96ST3 Paired amphipathic helix protein Sin3aPaired amphipathic helix protein Sin3a SIN3ASIN3A Not FoundNot Found HighHigh Q68DE3Q68DE3 Basic helix-loop-helix domain-containing protein USF3Basic helix-loop-helix domain-containing protein USF3 USF3USF3 Not FoundNot Found HighHigh Q15800Q15800 Methylsterol monooxygenase 1Methylsterol monooxygenase 1 MSMO1MSMO1 Not FoundNot Found HighHigh O00187O00187 Mannan-binding lectin serine protease 2Mannan-binding lectin serine protease 2 MASP2MASP2 Not FoundNot Found HighHigh Q9UIL1Q9UIL1 Short coiled-coil proteinShort coiled-coil protein SCOCSCOC Not FoundNot Found HighHigh Q76I76Q76I76 Protein phosphatase Slingshot homolog 2Protein phosphatase Slingshot homolog 2 SSH2SSH2 Not FoundNot Found HighHigh Q9Y6X6Q9Y6X6 Unconventional myosin-XVIUnconventional myosin-XVI MYO16MYO16 Not FoundNot Found HighHigh Q9H0E9Q9H0E9 Bromodomain-containing protein 8Bromodomain-containing protein 8 BRD8BRD8 Not FoundNot Found HighHigh Q5GLZ8Q5GLZ8 Probable E3 ubiquitin-protein ligase HERC4Probable E3 ubiquitin-protein ligase HERC4 HERC4HERC4 Not FoundNot Found HighHigh Q15811Q15811 Intersectin-1Intersectin-1 ITSN1ITSN1 Not FoundNot Found HighHigh Q96EK7Q96EK7 Constitutive coactivator of peroxisome proliferator-activated receptor gammaConstitutive coactivator of peroxisome proliferator-activated receptor gamma FAM120BFAM120B Not FoundNot Found HighHigh Q9H300Q9H300 Presenilins-associated rhomboid-like protein, mitochondrialPresenilins-associated rhomboid-like protein, mitochondrial PARLPARL Not FoundNot Found HighHigh Q92508Q92508 Piezo-type mechanosensitive ion channel component 1Piezo-type mechanosensitive ion channel component 1 PIEZO1PIEZO1 Not FoundNot Found HighHigh Q15223Q15223 Nectin-1Nectin-1 NECTIN1NECTIN1 Not FoundNot Found HighHigh O00408O00408 cGMP-dependent 3',5'-cyclic phosphodiesterasecGMP-dependent 3',5'-cyclic phosphodiesterase PDE2APDE2A Not FoundNot Found HighHigh Q8TDN4Q8TDN4 CDK5 and ABL1 enzyme substrate 1CDK5 and ABL1 enzyme substrate 1 CABLES1CABLES1 Not FoundNot Found HighHigh Q8WZ69Q8WZ69 Putative uncharacterized protein C11orf40Putative uncharacterized protein C11orf40 C11orf40C11orf40 Not FoundNot Found HighHigh Q15758Q15758 Neutral amino acid transporter B(0)Neutral amino acid transporter B(0) SLC1A5SLC1A5 Not FoundNot Found HighHigh P25098P25098 Beta-adrenergic receptor kinase 1Beta-adrenergic receptor kinase 1 GRK2GRK2 Not FoundNot Found HighHigh O14775O14775 Guanine nucleotide-binding protein subunit beta-5Guanine nucleotide-binding protein subunit beta-5 GNB5GNB5 Not FoundNot Found HighHigh Q96M86Q96M86 Dynein heavy chain domain-containing protein 1Dynein heavy chain domain-containing protein 1 DNHD1DNHD1 Not FoundNot Found HighHigh P16870P16870 Carboxypeptidase ECarboxypeptidase E CPECPE Not FoundNot Found HighHigh Q96Q04Q96Q04 Serine/threonine-protein kinase LMTK3Serine/threonine-protein kinase LMTK3 LMTK3LMTK3 Not FoundNot Found HighHigh P49184P49184 Deoxyribonuclease-1-like 1Deoxyribonuclease-1-like 1 DNASE1L1DNASE1L1 Not FoundNot Found HighHigh Q8IXH7Q8IXH7 Negative elongation factor C/DNegative elongation factor C/D NELFCDNELFCD Not FoundNot Found HighHigh Q9Y5E8Q9Y5E8 Protocadherin beta-15Protocadherin beta-15 PCDHB15PCDHB15 Not FoundNot Found HighHigh Q96KN7Q96KN7 X-linked retinitis pigmentosa GTPase regulator-interacting protein 1X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 RPGRIP1RPGRIP1 Not FoundNot Found HighHigh Q9H0T7Q9H0T7 Ras-related protein Rab-17Ras-related protein Rab-17 RAB17RAB17 Not FoundNot Found HighHigh

이 영역의 단백질은 2개의 조직에서 차별적으로 발현되어 바이오마커로 활용할 수 있을 것으로 기대된다.Proteins in this region are differentially expressed in two tissues and are expected to be used as biomarkers.

또한, 도 3에 나타난 바와 같이, NIFTP와 침윤성 EFVPTC의 조직시료의 2번 반복 측정한 각 수행에 대한 정량화된 단백질의 abundance를 box plot으로 나타내었다. 도 3의 box polt 및 correlation plot을 통하여 전체적인 단백질의 정량 값의 분포를 볼 수 있고 유사한 수준의 값을 나타낸다. 또한 각 technical replication에서도 높은 재현성을 보이는 것으로 나타났다.In addition, as shown in FIG. 3, the abundance of the quantified protein for each of the two repeated measurements of the tissue samples of NIFTP and invasive EFVPTC was shown as a box plot. Through the box polt and correlation plot of FIG. 3, the distribution of the overall protein quantification values can be seen and values of similar levels are shown. In addition, it was found to exhibit high reproducibility in each technical replication.

또한, 도 4에 나타난 바와 같이, 총 3,696개 단백질의 4개 시료에 대한 Hierarchical clustering 분석 결과를 확인하였다. clustering 분석을 통해 두 시료간의 차이를 나타내는 단백질을 한눈에 확인할 수 있었으며, 이러한 정량적 차이가 생물학적 의미와 연결이 되어있을 것으로 예상하였다.In addition, as shown in FIG. 4, the results of hierarchical clustering analysis for 4 samples of a total of 3,696 proteins were confirmed. Through clustering analysis, proteins representing the difference between the two samples could be identified at a glance, and this quantitative difference was expected to be linked to biological significance.

또한, 도 5에 나타난 바와 같이, volcano plot 분석을 통해서 NIFTP에 유의미하게 높게 발현되는 169개 단백질과 침윤성 EFVPTC에 유의미하게 높게 발현되는 237개 단백질을 확인하였으며, 그를 표 3 및 표 4에 기재하였다.In addition, as shown in FIG. 5, through volcano plot analysis, 169 proteins that were significantly expressed in NIFTP and 237 proteins that were significantly expressed in invasive EFVPTC were identified, and are described in Tables 3 and 4.

침윤성 EFVPTC에 유의미하게 높게 발현되는 237개 단백질237 proteins that are significantly highly expressed in invasive EFVPTC AccessionAccession ProteinNameProteinName GeneNameGeneName Fc:(NIFTP)/(EFVPTC)Fc:(NIFTP)/(EFVPTC) Adj_P-Value:Adj_P-Value: P54922P54922 [Protein ADP-ribosylarginine] hydrolase[Protein ADP-ribosylarginine] hydrolase ADPRHADPRH 0.0010.001 1.69E-161.69E-16 Q4U2R6Q4U2R6 39S ribosomal protein L51, mitochondrial39S ribosomal protein L51, mitochondrial MRPL51MRPL51 0.0010.001 1.69E-161.69E-16 P49914P49914 5-formyltetrahydrofolate cyclo-ligase5-formyltetrahydrofolate cyclo-ligase MTHFSMTHFS 0.0010.001 1.69E-161.69E-16 Q9H2P0Q9H2P0 Activity-dependent neuroprotector homeobox proteinActivity-dependent neuroprotector homeobox protein ADNPADNP 0.0010.001 1.69E-161.69E-16 P03950P03950 AngiogeninAngiogenin ANGANG 0.0010.001 1.69E-161.69E-16 Q9H2U1Q9H2U1 ATP-dependent RNA helicase DHX36ATP-dependent RNA helicase DHX36 DHX36DHX36 0.0010.001 1.69E-161.69E-16 Q68CP9Q68CP9 AT-rich interactive domain-containing protein 2AT-rich interactive domain-containing protein 2 ARID2ARID2 0.0010.001 1.69E-161.69E-16 P49407P49407 Beta-arrestin-1Beta-arrestin-1 ARRB1ARRB1 0.0010.001 1.69E-161.69E-16 Q7Z5Y6Q7Z5Y6 Bone morphogenetic protein 8ABone morphogenetic protein 8A BMP8ABMP8A 0.0010.001 1.69E-161.69E-16 O43866O43866 CD5 antigen-likeCD5 antigen-like CD5LCD5L 0.0010.001 1.69E-161.69E-16 Q96S66Q96S66 Chloride channel CLIC-like protein 1Chloride channel CLIC-like protein 1 CLCC1CLCC1 0.0010.001 1.69E-161.69E-16 Q9P2M7Q9P2M7 CingulinCingulin CGNCGN 0.0010.001 1.69E-161.69E-16 Q05048Q05048 Cleavage stimulation factor subunit 1Cleavage stimulation factor subunit 1 CSTF1CSTF1 0.0010.001 1.69E-161.69E-16 P25940P25940 Collagen alpha-3(V) chainCollagen alpha-3(V) chain COL5A3COL5A3 0.0010.001 1.69E-161.69E-16 Q9UBW8Q9UBW8 COP9 signalosome complex subunit 7aCOP9 signalosome complex subunit 7a COPS7ACOPS7A 0.0010.001 1.69E-161.69E-16 Q9NRF8Q9NRF8 CTP synthase 2CTP synthase 2 CTPS2CTPS2 0.0010.001 1.69E-161.69E-16 P15954P15954 Cytochrome c oxidase subunit 7C, mitochondrialCytochrome c oxidase subunit 7C, mitochondrial COX7CCOX7C 0.0010.001 1.69E-161.69E-16 P49902P49902 Cytosolic purine 5'-nucleotidaseCytosolic purine 5'-nucleotidase NT5C2NT5C2 0.0010.001 1.69E-161.69E-16 Q8N465Q8N465 D-2-hydroxyglutarate dehydrogenase, mitochondrialD-2-hydroxyglutarate dehydrogenase, mitochondrial D2HGDHD2HGDH 0.0010.001 1.69E-161.69E-16 Q8N5I4Q8N5I4 Dehydrogenase/reductase SDR family member on chromosome XDehydrogenase/reductase SDR family member on chromosome X DHRSXDHRSX 0.0010.001 1.69E-161.69E-16 P06746P06746 DNA polymerase betaDNA polymerase beta POLBPOLB 0.0010.001 1.69E-161.69E-16 Q9H3Z4Q9H3Z4 DnaJ homolog subfamily C member 5DnaJ homolog subfamily C member 5 DNAJC5DNAJC5 0.0010.001 1.69E-161.69E-16 Q86Y56Q86Y56 Dynein assembly factor 5, axonemalDynein assembly factor 5, axonemal DNAAF5DNAAF5 0.0010.001 1.69E-161.69E-16 P63172P63172 Dynein light chain Tctex-type 1Dynein light chain Tctex-type 1 DYNLT1DYNLT1 0.0010.001 1.69E-161.69E-16 Q8IZA0Q8IZA0 Dyslexia-associated protein KIAA0319-like proteinDyslexia-associated protein KIAA0319-like protein KIAA0319LKIAA0319L 0.0010.001 1.69E-161.69E-16 Q9P2P5Q9P2P5 E3 ubiquitin-protein ligase HECW2E3 ubiquitin-protein ligase HECW2 HECW2HECW2 0.0010.001 1.69E-161.69E-16 Q96C19Q96C19 EF-hand domain-containing protein D2EF-hand domain-containing protein D2 EFHD2EFHD2 0.0010.001 1.69E-161.69E-16 Q5NDL2Q5NDL2 EGF domain-specific O-linked N-acetylglucosamine transferaseEGF domain-specific O-linked N-acetylglucosamine transferase EOGTEOGT 0.0010.001 1.69E-161.69E-16 Q99962Q99962 Endophilin-A1Endophilin-A1 SH3GL2SH3GL2 0.0010.001 1.69E-161.69E-16 Q86YB8Q86YB8 ERO1-like protein betaERO1-like protein beta ERO1BERO1B 0.0010.001 1.69E-161.69E-16 P23588P23588 Eukaryotic translation initiation factor 4BEukaryotic translation initiation factor 4B EIF4BEIF4B 0.0010.001 1.69E-161.69E-16 O60841O60841 Eukaryotic translation initiation factor 5BEukaryotic translation initiation factor 5B EIF5BEIF5B 0.0010.001 1.69E-161.69E-16 P05413P05413 Fatty acid-binding protein, heartFatty acid-binding protein, heart FABP3FABP3 0.0010.001 1.69E-161.69E-16 Q6P4F2Q6P4F2 Ferredoxin-2, mitochondrialFerredoxin-2, mitochondrial FDX2FDX2 0.0010.001 1.69E-161.69E-16 O00757O00757 Fructose-1,6-bisphosphatase isozyme 2Fructose-1,6-bisphosphatase isozyme 2 FBP2FBP2 0.0010.001 1.69E-161.69E-16 Q2TAA5Q2TAA5 GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferaseGDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase ALG11ALG11 0.0010.001 1.69E-161.69E-16 Q9NS00Q9NS00 Glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1Glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1 C1GALT1C1GALT1 0.0010.001 1.69E-161.69E-16 O75063O75063 Glycosaminoglycan xylosylkinaseGlycosaminoglycan xylosylkinase FAM20BFAM20B 0.0010.001 1.69E-161.69E-16 O00461O00461 Golgi integral membrane protein 4Golgi integral membrane protein 4 GOLIM4GOLIM4 0.0010.001 1.69E-161.69E-16 Q9H4A5Q9H4A5 Golgi phosphoprotein 3-likeGolgi phosphoprotein 3-like GOLPH3LGOLPH3L 0.0010.001 1.69E-161.69E-16 O14964O14964 Hepatocyte growth factor-regulated tyrosine kinase substrateHepatocyte growth factor-regulated tyrosine kinase substrate HGSHGS 0.0010.001 1.69E-161.69E-16 A0A0C4DH31A0A0C4DH31 Immunoglobulin heavy variable 1-18Immunoglobulin heavy variable 1-18 IGHV1-18IGHV1-18 0.0010.001 1.69E-161.69E-16 Q8N201Q8N201 Integrator complex subunit 1Integrator complex subunit 1 INTS1INTS1 0.0010.001 1.69E-161.69E-16 Q8TDD1-2Q8TDD1-2 Isoform 2 of ATP-dependent RNA helicase DDX54Isoform 2 of ATP-dependent RNA helicase DDX54 DDX54DDX54 0.0010.001 1.69E-161.69E-16 Q9H0R8-2Q9H0R8-2 Isoform 2 of Gamma-aminobutyric acid receptor-associated protein-like 1Isoform 2 of Gamma-aminobutyric acid receptor-associated protein-like 1 GABARAPL1GABARAPL1 0.0010.001 1.69E-161.69E-16 O43847-2O43847-2 Isoform 2 of NardilysinIsoform 2 of Nardilysin NRDCNRDC 0.0010.001 1.69E-161.69E-16 Q5EBL8-2Q5EBL8-2 Isoform 2 of PDZ domain-containing protein 11Isoform 2 of PDZ domain-containing protein 11 PDZD11PDZD11 0.0010.001 1.69E-161.69E-16 Q6VY07-2Q6VY07-2 Isoform 2 of Phosphofurin acidic cluster sorting protein 1Isoform 2 of Phosphofurin acidic cluster sorting protein 1 PACS1PACS1 0.0010.001 1.69E-161.69E-16 Q14558-2Q14558-2 Isoform 2 of Phosphoribosyl pyrophosphate synthase-associated protein 1Isoform 2 of Phosphoribosyl pyrophosphate synthase-associated protein 1 PRPSAP1PRPSAP1 0.0010.001 1.69E-161.69E-16 Q8IWL2-2Q8IWL2-2 Isoform 2 of Pulmonary surfactant-associated protein A1Isoform 2 of Pulmonary surfactant-associated protein A1 SFTPA1SFTPA1 0.0010.001 1.69E-161.69E-16 O00559-2O00559-2 Isoform 2 of Receptor-binding cancer antigen expressed on SiSo cellsIsoform 2 of Receptor-binding cancer antigen expressed on SiSo cells EBAG9EBAG9 0.0010.001 1.69E-161.69E-16 Q14247-2Q14247-2 Isoform 2 of Src substrate cortactinIsoform 2 of Src substrate cortactin CTTNCTTN 0.0010.001 1.69E-161.69E-16 O94911-3O94911-3 Isoform 3 of ATP-binding cassette sub-family A member 8Isoform 3 of ATP-binding cassette sub-family A member 8 ABCA8ABCA8 0.0010.001 1.69E-161.69E-16 A0MZ66-3A0MZ66-3 Isoform 3 of Shootin-1Isoform 3 of Shootin-1 SHTN1SHTN1 0.0010.001 1.69E-161.69E-16 P61077-3P61077-3 Isoform 3 of Ubiquitin-conjugating enzyme E2 D3Isoform 3 of Ubiquitin-conjugating enzyme E2 D3 UBE2D3UBE2D3 0.0010.001 1.69E-161.69E-16 Q6ICL3-4Q6ICL3-4 Isoform 4 of Transport and Golgi organization protein 2 homologIsoform 4 of Transport and Golgi organization protein 2 homolog TANGO2TANGO2 0.0010.001 1.69E-161.69E-16 Q05397-5Q05397-5 Isoform 5 of Focal adhesion kinase 1Isoform 5 of Focal adhesion kinase 1 PTK2PTK2 0.0010.001 1.69E-161.69E-16 P35658-5P35658-5 Isoform 5 of Nuclear pore complex protein Nup214Isoform 5 of Nuclear pore complex protein Nup214 NUP214NUP214 0.0010.001 1.69E-161.69E-16 O00142-6O00142-6 Isoform 6 of Thymidine kinase 2, mitochondrialIsoform 6 of Thymidine kinase 2, mitochondrial TK2TK2 0.0010.001 1.69E-161.69E-16 Q9Y6F6-7Q9Y6F6-7 Isoform 7 of Protein MRVI1Isoform 7 of Protein MRVI1 MRVI1MRVI1 0.0010.001 1.69E-161.69E-16 Q9BWU0Q9BWU0 KanadaptinKanadaptin SLC4A1APSLC4A1AP 0.0010.001 1.69E-161.69E-16 Q16850Q16850 Lanosterol 14-alpha demethylaseLanosterol 14-alpha demethylase CYP51A1CYP51A1 0.0010.001 1.69E-161.69E-16 Q14728Q14728 Major facilitator superfamily domain-containing protein 10Major facilitator superfamily domain-containing protein 10 MFSD10MFSD10 0.0010.001 1.69E-161.69E-16 P01033P01033 Metalloproteinase inhibitor 1Metalloproteinase inhibitor 1 TIMP1TIMP1 0.0010.001 1.69E-161.69E-16 O94776O94776 Metastasis-associated protein MTA2Metastasis-associated protein MTA2 MTA2MTA2 0.0010.001 1.69E-161.69E-16 Q9Y3A3Q9Y3A3 MOB-like protein phoceinMOB-like protein phocein MOB4MOB4 0.0010.001 1.69E-161.69E-16 Q13613Q13613 Myotubularin-related protein 1Myotubularin-related protein 1 MTMR1MTMR1 0.0010.001 1.69E-161.69E-16 Q8NFP9Q8NFP9 NeurobeachinNeurobeachin NBEANBEA 0.0010.001 1.69E-161.69E-16 P61601P61601 Neurocalcin-deltaNeurocalcin-delta NCALDNCALD 0.0010.001 1.69E-161.69E-16 Q9NRN5Q9NRN5 Olfactomedin-like protein 3Olfactomedin-like protein 3 OLFML3OLFML3 0.0010.001 1.69E-161.69E-16 Q8NGA1Q8NGA1 Olfactory receptor 1M1Olfactory receptor 1M1 OR1M1OR1M1 0.0010.001 1.69E-161.69E-16 P40855P40855 Peroxisomal biogenesis factor 19Peroxisomal biogenesis factor 19 PEX19PEX19 0.0010.001 1.69E-161.69E-16 Q9NW64Q9NW64 Pre-mRNA-splicing factor RBM22Pre-mRNA-splicing factor RBM22 RBM22RBM22 0.0010.001 1.69E-161.69E-16 Q96SM3Q96SM3 Probable carboxypeptidase X1Probable carboxypeptidase X1 CPXM1CPXM1 0.0010.001 1.69E-161.69E-16 Q9NPF4Q9NPF4 Probable tRNA N6-adenosine threonylcarbamoyltransferaseProbable tRNA N6-adenosine threonylcarbamoyltransferase OSGEPOSGEP 0.0010.001 1.69E-161.69E-16 Q9NVM1Q9NVM1 Protein eva-1 homolog BProtein eva-1 homolog B EVA1BEVA1B 0.0010.001 1.69E-161.69E-16 Q86VS8Q86VS8 Protein Hook homolog 3Protein Hook homolog 3 HOOK3HOOK3 0.0010.001 1.69E-161.69E-16 O14974O14974 Protein phosphatase 1 regulatory subunit 12AProtein phosphatase 1 regulatory subunit 12A PPP1R12APPP1R12A 0.0010.001 1.69E-161.69E-16 Q86U86Q86U86 Protein polybromo-1Protein polybromo-1 PBRM1PBRM1 0.0010.001 1.69E-161.69E-16 Q9H0U4Q9H0U4 Ras-related protein Rab-1BRas-related protein Rab-1B RAB1BRAB1B 0.0010.001 1.69E-161.69E-16 P51151P51151 Ras-related protein Rab-9ARas-related protein Rab-9A RAB9ARAB9A 0.0010.001 1.69E-161.69E-16 O43924O43924 Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit deltaRetinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta PDE6DPDE6D 0.0010.001 1.69E-161.69E-16 P07998P07998 Ribonuclease pancreaticRibonuclease pancreatic RNASE1RNASE1 0.0010.001 1.69E-161.69E-16 Q96T51Q96T51 RUN and FYVE domain-containing protein 1RUN and FYVE domain-containing protein 1 RUFY1RUFY1 0.0010.001 1.69E-161.69E-16 Q8N474Q8N474 Secreted frizzled-related protein 1Secreted frizzled-related protein 1 SFRP1SFRP1 0.0010.001 1.69E-161.69E-16 Q96QR1Q96QR1 Secretoglobin family 3A member 1Secretoglobin family 3A member 1 SCGB3A1SCGB3A1 0.0010.001 1.69E-161.69E-16 Q13501Q13501 Sequestosome-1Sequestosome-1 SQSTM1SQSTM1 0.0010.001 1.69E-161.69E-16 O75716O75716 Serine/threonine-protein kinase 16Serine/threonine-protein kinase 16 STK16STK16 0.0010.001 1.69E-161.69E-16 Q9BRF8Q9BRF8 Serine/threonine-protein phosphatase CPPED1Serine/threonine-protein phosphatase CPPED1 CPPED1CPPED1 0.0010.001 1.69E-161.69E-16 Q8WVQ1Q8WVQ1 Soluble calcium-activated nucleotidase 1Soluble calcium-activated nucleotidase 1 CANT1CANT1 0.0010.001 1.69E-161.69E-16 Q96SI9Q96SI9 Spermatid perinuclear RNA-binding proteinSpermatid perinuclear RNA-binding protein STRBPSTRBP 0.0010.001 1.69E-161.69E-16 O60687O60687 Sushi repeat-containing protein SRPX2Sushi repeat-containing protein SRPX2 SRPX2SRPX2 0.0010.001 1.69E-161.69E-16 Q96A49Q96A49 Synapse-associated protein 1Synapse-associated protein 1 SYAP1SYAP1 0.0010.001 1.69E-161.69E-16 Q8TB96Q8TB96 T-cell immunomodulatory proteinT-cell immunomodulatory protein ITFG1ITFG1 0.0010.001 1.69E-161.69E-16 Q9UQP3Q9UQP3 Tenascin-NTenascin-N TNNTNN 0.0010.001 1.69E-161.69E-16 Q6I9Y2Q6I9Y2 THO complex subunit 7 homologTHO complex subunit 7 homolog THOC7THOC7 0.0010.001 1.69E-161.69E-16 P35443P35443 Thrombospondin-4Thrombospondin-4 THBS4THBS4 0.0010.001 1.69E-161.69E-16 Q9NUM4Q9NUM4 Transmembrane protein 106BTransmembrane protein 106B TMEM106BTMEM106B 0.0010.001 1.69E-161.69E-16 O14562O14562 Ubiquitin domain-containing protein UBFD1Ubiquitin domain-containing protein UBFD1 UBFD1UBFD1 0.0010.001 1.69E-161.69E-16 Q9BZV1Q9BZV1 UBX domain-containing protein 6UBX domain-containing protein 6 UBXN6UBXN6 0.0010.001 1.69E-161.69E-16 Q5T6V5Q5T6V5 UPF0553 protein C9orf64UPF0553 protein C9orf64 C9orf64C9orf64 0.0010.001 1.69E-161.69E-16 Q9BZF9Q9BZF9 Uveal autoantigen with coiled-coil domains and ankyrin repeatsUveal autoantigen with coiled-coil domains and ankyrin repeats UACAUACA 0.0010.001 1.69E-161.69E-16 Q641Q2Q641Q2 WASH complex subunit 2AWASH complex subunit 2A WASHC2AWASHC2A 0.0010.001 1.69E-161.69E-16 Q9H1Z4Q9H1Z4 WD repeat-containing protein 13WD repeat-containing protein 13 WDR13WDR13 0.0010.001 1.69E-161.69E-16 O75152O75152 Zinc finger CCCH domain-containing protein 11AZinc finger CCCH domain-containing protein 11A ZC3H11AZC3H11A 0.0010.001 1.69E-161.69E-16 Q9UGR2Q9UGR2 Zinc finger CCCH domain-containing protein 7BZinc finger CCCH domain-containing protein 7B ZC3H7BZC3H7B 0.0010.001 1.69E-161.69E-16 O43414O43414 ERI1 exoribonuclease 3ERI1 exoribonuclease 3 ERI3ERI3 0.0190.019 1.69E-161.69E-16 P62891P62891 60S ribosomal protein L3960S ribosomal protein L39 RPL39RPL39 0.0240.024 1.69E-161.69E-16 O75438-2O75438-2 Isoform 2 of NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1Isoform 2 of NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 NDUFB1NDUFB1 0.0260.026 1.69E-161.69E-16 Q15366-2Q15366-2 Isoform 2 of Poly(rC)-binding protein 2Isoform 2 of Poly(rC)-binding protein 2 PCBP2PCBP2 0.0310.031 9.11E-119.11E-11 Q10588Q10588 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 2ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 2 BST1BST1 0.0480.048 1.71E-111.71E-11 P82909P82909 28S ribosomal protein S36, mitochondrial28S ribosomal protein S36, mitochondrial MRPS36MRPS36 0.050.05 1.69E-161.69E-16 Q8IWZ3-6Q8IWZ3-6 Isoform 6 of Ankyrin repeat and KH domain-containing protein 1Isoform 6 of Ankyrin repeat and KH domain-containing protein 1 ANKHD1ANKHD1 0.0560.056 5.75E-115.75E-11 Q9Y241Q9Y241 HIG1 domain family member 1A, mitochondrialHIG1 domain family member 1A, mitochondrial HIGD1AHIGD1A 0.0590.059 1.71E-081.71E-08 Q96QR8Q96QR8 Transcriptional activator protein Pur-betaTranscriptional activator protein Pur-beta PURBPURB 0.0590.059 4.53E-124.53E-12 O43294O43294 Transforming growth factor beta-1-induced transcript 1 proteinTransforming growth factor beta-1-induced transcript 1 protein TGFB1I1TGFB1I1 0.0690.069 6.76E-086.76E-08 Q14657Q14657 EKC/KEOPS complex subunit LAGE3EKC/KEOPS complex subunit LAGE3 LAGE3LAGE3 0.070.07 1.47E-061.47E-06 Q8NF91Q8NF91 Nesprin-1Nesprin-1 SYNE1SYNE1 0.0750.075 5.62E-075.62E-07 Q96S15Q96S15 WD repeat-containing protein 24WD repeat-containing protein 24 WDR24WDR24 0.0750.075 7.18E-067.18E-06 Q05209Q05209 Tyrosine-protein phosphatase non-receptor type 12Tyrosine-protein phosphatase non-receptor type 12 PTPN12PTPN12 0.080.08 8.80E-068.80E-06 P0C7P0P0C7P0 CDGSH iron-sulfur domain-containing protein 3, mitochondrialCDGSH iron-sulfur domain-containing protein 3, mitochondrial CISD3CISD3 0.0850.085 6.18E-096.18E-09 P19022P19022 Cadherin-2Cadherin-2 CDH2CDH2 0.0940.094 4.61E-124.61E-12 Q9BZC7-3Q9BZC7-3 Isoform 3 of ATP-binding cassette sub-family A member 2Isoform 3 of ATP-binding cassette sub-family A member 2 ABCA2ABCA2 0.0960.096 8.28E-058.28E-05 A0A0A0MRZ8A0A0A0MRZ8 Immunoglobulin kappa variable 3D-11Immunoglobulin kappa variable 3D-11 IGKV3D-11IGKV3D-11 0.1040.104 2.96E-102.96E-10 Q6ZU80Q6ZU80 Centrosomal protein of 128 kDaCentrosomal protein of 128 kDa CEP128CEP128 0.1060.106 9.32E-059.32E-05 Q86TM6Q86TM6 E3 ubiquitin-protein ligase synoviolinE3 ubiquitin-protein ligase synoviolin SYVN1SYVN1 0.1090.109 2.94E-052.94E-05 O94769O94769 Extracellular matrix protein 2Extracellular matrix protein 2 ECM2ECM2 0.1140.114 1.01E-051.01E-05 O75937O75937 DnaJ homolog subfamily C member 8DnaJ homolog subfamily C member 8 DNAJC8DNAJC8 0.1160.116 5.73E-065.73E-06 Q66K66Q66K66 Transmembrane protein 198Transmembrane protein 198 TMEM198TMEM198 0.1180.118 4.02E-094.02E-09 Q15813-2Q15813-2 Isoform 2 of Tubulin-specific chaperone EIsoform 2 of Tubulin-specific chaperone E TBCETBCE 0.1210.121 1.11E-041.11E-04 P15088P15088 Mast cell carboxypeptidase AMast cell carboxypeptidase A CPA3CPA3 0.1310.131 5.41E-095.41E-09 Q96R05Q96R05 Retinoid-binding protein 7Retinoid-binding protein 7 RBP7RBP7 0.1330.133 2.23E-042.23E-04 P13929P13929 Beta-enolaseBeta-enolase ENO3ENO3 0.1350.135 8.77E-098.77E-09 Q9Y3C8Q9Y3C8 Ubiquitin-fold modifier-conjugating enzyme 1Ubiquitin-fold modifier-conjugating enzyme 1 UFC1UFC1 0.140.14 1.46E-071.46E-07 Q92959Q92959 Solute carrier organic anion transporter family member 2A1Solute carrier organic anion transporter family member 2A1 SLCO2A1SLCO2A1 0.1410.141 8.20E-068.20E-06 Q9BTE6-3Q9BTE6-3 Isoform 3 of Alanyl-tRNA editing protein Aarsd1Isoform 3 of Alanyl-tRNA editing protein Aarsd1 AARSD1AARSD1 0.1430.143 9.36E-049.36E-04 P19652P19652 Alpha-1-acid glycoprotein 2Alpha-1-acid glycoprotein 2 ORM2ORM2 0.1440.144 1.84E-101.84E-10 Q9UN86Q9UN86 Ras GTPase-activating protein-binding protein 2Ras GTPase-activating protein-binding protein 2 G3BP2G3BP2 0.1450.145 8.97E-058.97E-05 Q14684Q14684 Ribosomal RNA processing protein 1 homolog BRibosomal RNA processing protein 1 homolog B RRP1BRRP1B 0.1450.145 1.98E-031.98E-03 Q9UKP4Q9UKP4 A disintegrin and metalloproteinase with thrombospondin motifs 7A disintegrin and metalloproteinase with thrombospondin motifs 7 ADAMTS7ADAMTS7 0.150.15 1.56E-031.56E-03 Q9NYQ6Q9NYQ6 Cadherin EGF LAG seven-pass G-type receptor 1Cadherin EGF LAG seven-pass G-type receptor 1 CELSR1CELSR1 0.1620.162 9.87E-049.87E-04 P16104P16104 Histone H2AXHistone H2AX H2AFXH2AFX 0.1640.164 3.81E-053.81E-05 O00541O00541 Pescadillo homologPescadillo homolog PES1PES1 0.1650.165 2.49E-042.49E-04 P11279P11279 Lysosome-associated membrane glycoprotein 1Lysosome-associated membrane glycoprotein 1 LAMP1LAMP1 0.1660.166 1.14E-091.14E-09 Q14061Q14061 Cytochrome c oxidase copper chaperoneCytochrome c oxidase copper chaperone COX17COX17 0.1690.169 9.08E-049.08E-04 Q53EP0Q53EP0 Fibronectin type III domain-containing protein 3BFibronectin type III domain-containing protein 3B FNDC3BFNDC3B 0.1840.184 5.31E-035.31E-03 P02763P02763 Alpha-1-acid glycoprotein 1Alpha-1-acid glycoprotein 1 ORM1ORM1 0.1890.189 6.50E-086.50E-08 Q99442Q99442 Translocation protein SEC62Translocation protein SEC62 SEC62SEC62 0.1910.191 3.10E-033.10E-03 P13987P13987 CD59 glycoproteinCD59 glycoprotein CD59CD59 0.1930.193 4.96E-084.96E-08 P51911P51911 Calponin-1Calponin-1 CNN1CNN1 0.2060.206 2.24E-032.24E-03 P05534P05534 HLA class I histocompatibility antigen, A-24 alpha chainHLA class I histocompatibility antigen, A-24 alpha chain HLA-AHLA-A 0.2060.206 7.66E-077.66E-07 Q969E2Q969E2 Secretory carrier-associated membrane protein 4Secretory carrier-associated membrane protein 4 SCAMP4SCAMP4 0.2060.206 3.18E-053.18E-05 Q9BSH4Q9BSH4 Translational activator of cytochrome c oxidase 1Translational activator of cytochrome c oxidase 1 TACO1TACO1 0.2140.214 3.16E-033.16E-03 Q7L014Q7L014 Probable ATP-dependent RNA helicase DDX46Probable ATP-dependent RNA helicase DDX46 DDX46DDX46 0.2160.216 3.79E-033.79E-03 Q9H832Q9H832 Ubiquitin-conjugating enzyme E2 ZUbiquitin-conjugating enzyme E2 Z UBE2ZUBE2Z 0.2190.219 9.16E-039.16E-03 Q04446Q04446 1,4-alpha-glucan-branching enzyme1,4-alpha-glucan-branching enzyme GBE1GBE1 0.2210.221 3.44E-033.44E-03 P02750P02750 Leucine-rich alpha-2-glycoproteinLeucine-rich alpha-2-glycoprotein LRG1LRG1 0.2210.221 7.43E-057.43E-05 Q13564-4Q13564-4 Isoform 4 of NEDD8-activating enzyme E1 regulatory subunitIsoform 4 of NEDD8-activating enzyme E1 regulatory subunit NAE1NAE1 0.2220.222 3.12E-033.12E-03 Q9NRY4Q9NRY4 Rho GTPase-activating protein 35Rho GTPase-activating protein 35 ARHGAP35ARHGAP35 0.2260.226 2.79E-022.79E-02 Q9UH65Q9UH65 Switch-associated protein 70Switch-associated protein 70 SWAP70SWAP70 0.2260.226 3.22E-033.22E-03 Q5S007Q5S007 Leucine-rich repeat serine/threonine-protein kinase 2Leucine-rich repeat serine/threonine-protein kinase 2 LRRK2LRRK2 0.2330.233 2.85E-022.85E-02 Q9UK59Q9UK59 Lariat debranching enzymeLariat debranching enzyme DBR1DBR1 0.2350.235 6.09E-036.09E-03 O60826O60826 Coiled-coil domain-containing protein 22Coiled-coil domain-containing protein 22 CCDC22CCDC22 0.2380.238 6.55E-036.55E-03 Q02539Q02539 Histone H1.1Histone H1.1 HIST1H1AHIST1H1A 0.2380.238 1.97E-021.97E-02 P55083-2P55083-2 Isoform 2 of Microfibril-associated glycoprotein 4Isoform 2 of Microfibril-associated glycoprotein 4 MFAP4MFAP4 0.2420.242 7.50E-037.50E-03 P07988P07988 Pulmonary surfactant-associated protein BPulmonary surfactant-associated protein B SFTPBSFTPB 0.2450.245 5.45E-055.45E-05 Q9H3U7-2Q9H3U7-2 Isoform 2 of SPARC-related modular calcium-binding protein 2Isoform 2 of SPARC-related modular calcium-binding protein 2 SMOC2SMOC2 0.2460.246 1.28E-021.28E-02 P52895P52895 Aldo-keto reductase family 1 member C2Aldo-keto reductase family 1 member C2 AKR1C2AKR1C2 0.2510.251 9.92E-049.92E-04 Q14766-4Q14766-4 Isoform 4 of Latent-transforming growth factor beta-binding protein 1Isoform 4 of Latent-transforming growth factor beta-binding protein 1 LTBP1LTBP1 0.260.26 1.22E-021.22E-02 Q13103Q13103 Secreted phosphoprotein 24Secreted phosphoprotein 24 SPP2SPP2 0.2610.261 2.27E-032.27E-03 Q02952Q02952 A-kinase anchor protein 12A-kinase anchor protein 12 AKAP12AKAP12 0.2660.266 1.26E-021.26E-02 P35659P35659 Protein DEKProtein DEK DEKDEK 0.2680.268 3.84E-043.84E-04 O00425O00425 Insulin-like growth factor 2 mRNA-binding protein 3Insulin-like growth factor 2 mRNA-binding protein 3 IGF2BP3IGF2BP3 0.2710.271 3.02E-053.02E-05 Q9NPH0Q9NPH0 Lysophosphatidic acid phosphatase type 6Lysophosphatidic acid phosphatase type 6 ACP6ACP6 0.2780.278 1.79E-021.79E-02 Q969G5Q969G5 Protein kinase C delta-binding proteinProtein kinase C delta-binding protein PRKCDBPPRKCDBP 0.2890.289 2.90E-022.90E-02 P00750P00750 Tissue-type plasminogen activatorTissue-type plasminogen activator PLATPLAT 0.2950.295 2.42E-022.42E-02 P50552P50552 Vasodilator-stimulated phosphoproteinVasodilator-stimulated phosphoprotein VASPVASP 0.2960.296 1.36E-021.36E-02 O75348O75348 V-type proton ATPase subunit G 1V-type proton ATPase subunit G 1 ATP6V1G1ATP6V1G1 0.2960.296 2.52E-032.52E-03 P09936P09936 Ubiquitin carboxyl-terminal hydrolase isozyme L1Ubiquitin carboxyl-terminal hydrolase isozyme L1 UCHL1UCHL1 0.3010.301 4.75E-024.75E-02 Q86T03-2Q86T03-2 Isoform 2 of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphataseIsoform 2 of Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase TMEM55BTMEM55B 0.3040.304 2.72E-022.72E-02 Q9NR12Q9NR12 PDZ and LIM domain protein 7PDZ and LIM domain protein 7 PDLIM7PDLIM7 0.3080.308 4.36E-024.36E-02 P53680P53680 AP-2 complex subunit sigmaAP-2 complex subunit sigma AP2S1AP2S1 0.3090.309 6.99E-036.99E-03 P16519P16519 Neuroendocrine convertase 2Neuroendocrine convertase 2 PCSK2PCSK2 0.310.31 3.43E-043.43E-04 O43570O43570 Carbonic anhydrase 12Carbonic anhydrase 12 CA12CA12 0.3140.314 2.43E-032.43E-03 P29762P29762 Cellular retinoic acid-binding protein 1Cellular retinoic acid-binding protein 1 CRABP1CRABP1 0.3210.321 2.87E-032.87E-03 P29992P29992 Guanine nucleotide-binding protein subunit alpha-11Guanine nucleotide-binding protein subunit alpha-11 GNA11GNA11 0.3250.325 1.09E-021.09E-02 Q99584Q99584 Protein S100-A13Protein S100-A13 S100A13S100A13 0.3250.325 6.95E-046.95E-04 P30711P30711 Glutathione S-transferase theta-1Glutathione S-transferase theta-1 GSTT1GSTT1 0.3280.328 7.09E-037.09E-03 Q01995Q01995 TransgelinTransgelin TAGLNTAGLN 0.3340.334 4.89E-044.89E-04 P09493-6P09493-6 Isoform 6 of Tropomyosin alpha-1 chainIsoform 6 of Tropomyosin alpha-1 chain TPM1TPM1 0.3350.335 4.85E-034.85E-03 P67936P67936 Tropomyosin alpha-4 chainTropomyosin alpha-4 chain TPM4TPM4 0.3360.336 5.05E-035.05E-03 Q9Y696Q9Y696 Chloride intracellular channel protein 4Chloride intracellular channel protein 4 CLIC4CLIC4 0.3390.339 1.64E-021.64E-02 P03973P03973 AntileukoproteinaseAntileukoproteinase SLPISLPI 0.340.34 3.73E-023.73E-02 Q9Y365Q9Y365 PTCP-like proteinPTCP-like protein STARD10STARD10 0.340.34 2.41E-022.41E-02 O75347O75347 Tubulin-specific chaperone ATubulin-specific chaperone A TBCATBCA 0.3420.342 1.03E-021.03E-02 P80723P80723 Brain acid soluble protein 1Brain acid soluble protein 1 BASP1BASP1 0.3530.353 7.50E-037.50E-03 P43652P43652 AfaminAfamin AFMAFM 0.3540.354 7.82E-037.82E-03 O95372O95372 Acyl-protein thioesterase 2Acyl-protein thioesterase 2 LYPLA2LYPLA2 0.360.36 3.34E-023.34E-02 Q13439-5Q13439-5 Isoform 5 of Golgin subfamily A member 4Isoform 5 of Golgin subfamily A member 4 GOLGA4GOLGA4 0.3610.361 4.87E-024.87E-02 Q9BXP5Q9BXP5 Serrate RNA effector molecule homologSerrate RNA effector molecule homolog SRRTSRRT 0.3640.364 1.82E-021.82E-02 P02768P02768 Serum albuminSerum albumin ALBALB 0.3780.378 4.75E-034.75E-03 P22413P22413 Ectonucleotide pyrophosphatase/phosphodiesterase family member 1Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 ENPP1ENPP1 0.3790.379 4.99E-034.99E-03 P25311P25311 Zinc-alpha-2-glycoproteinZinc-alpha-2-glycoprotein AZGP1AZGP1 0.3810.381 1.92E-021.92E-02 P02774-3P02774-3 Isoform 3 of Vitamin D-binding proteinIsoform 3 of Vitamin D-binding protein GCGC 0.3840.384 5.69E-035.69E-03 O95994O95994 Anterior gradient protein 2 homologAnterior gradient protein 2 homolog AGR2AGR2 0.3850.385 7.11E-037.11E-03 P09493-5P09493-5 Isoform 5 of Tropomyosin alpha-1 chainIsoform 5 of Tropomyosin alpha-1 chain TPM1TPM1 0.3870.387 4.47E-024.47E-02 P08240P08240 Signal recognition particle receptor subunit alphaSignal recognition particle receptor subunit alpha SRPRASRPRA 0.3870.387 3.54E-023.54E-02 P19827P19827 Inter-alpha-trypsin inhibitor heavy chain H1Inter-alpha-trypsin inhibitor heavy chain H1 ITIH1ITIH1 0.3910.391 7.05E-037.05E-03 P02765P02765 Alpha-2-HS-glycoproteinAlpha-2-HS-glycoprotein AHSGAHSG 0.3920.392 7.23E-037.23E-03 P20231P20231 Tryptase beta-2Tryptase beta-2 TPSB2TPSB2 0.3990.399 4.60E-034.60E-03 P06727P06727 Apolipoprotein A-IVApolipoprotein A-IV APOA4APOA4 0.40.4 9.15E-039.15E-03 Q96C23Q96C23 Aldose 1-epimeraseAldose 1-epimerase GALMGALM 0.4050.405 4.98E-024.98E-02 Q96BS2Q96BS2 Calcineurin B homologous protein 3Calcineurin B homologous protein 3 TESCTESC 0.4060.406 3.12E-023.12E-02 P09467P09467 Fructose-1,6-bisphosphatase 1Fructose-1,6-bisphosphatase 1 FBP1FBP1 0.4060.406 2.70E-022.70E-02 P09104P09104 Gamma-enolaseGamma-enolase ENO2ENO2 0.410.41 3.49E-023.49E-02 Q9NVS9Q9NVS9 Pyridoxine-5'-phosphate oxidasePyridoxine-5'-phosphate oxidase PNPOPNPO 0.4120.412 1.29E-021.29E-02 P01009P01009 Alpha-1-antitrypsinAlpha-1-antitrypsin SERPINA1SERPINA1 0.4140.414 1.36E-021.36E-02 P08962P08962 CD63 antigenCD63 antigen CD63CD63 0.4160.416 1.92E-021.92E-02 P02766P02766 TransthyretinTransthyretin TTRTTR 0.4170.417 1.48E-021.48E-02 Q9UBI6Q9UBI6 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 GNG12GNG12 0.4190.419 3.91E-023.91E-02 A0A0C4DH25A0A0C4DH25 Immunoglobulin kappa variable 3D-20Immunoglobulin kappa variable 3D-20 IGKV3D-20IGKV3D-20 0.4190.419 1.67E-021.67E-02 P01042P01042 Kininogen-1Kininogen-1 KNG1KNG1 0.4230.423 1.72E-021.72E-02 P43121P43121 Cell surface glycoprotein MUC18Cell surface glycoprotein MUC18 MCAMMCAM 0.4260.426 1.20E-021.20E-02 P27348P27348 14-3-3 protein theta14-3-3 protein theta YWHAQYWHAQ 0.4280.428 4.51E-024.51E-02 P07951-2P07951-2 Isoform 2 of Tropomyosin beta chainIsoform 2 of Tropomyosin beta chain TPM2TPM2 0.4280.428 1.93E-021.93E-02 P02647P02647 Apolipoprotein A-IApolipoprotein A-I APOA1APOA1 0.4310.431 2.04E-022.04E-02 Q9UBX5Q9UBX5 Fibulin-5Fibulin-5 FBLN5FBLN5 0.4320.432 1.39E-021.39E-02 P08697P08697 Alpha-2-antiplasminAlpha-2-antiplasmin SERPINF2SERPINF2 0.4330.433 4.49E-024.49E-02 P51888P51888 ProlarginProlargin PRELPPRELP 0.4340.434 2.22E-022.22E-02 P22105-4P22105-4 Isoform 5 of Tenascin-XIsoform 5 of Tenascin-X TNXBTNXB 0.4350.435 1.50E-021.50E-02 P80404P80404 4-aminobutyrate aminotransferase, mitochondrial4-aminobutyrate aminotransferase, mitochondrial ABATABAT 0.4370.437 2.38E-022.38E-02 P01008P01008 Antithrombin-IIIAntithrombin-III SERPINC1SERPINC1 0.4440.444 2.85E-022.85E-02 P09493P09493 Tropomyosin alpha-1 chainTropomyosin alpha-1 chain TPM1TPM1 0.4460.446 2.90E-022.90E-02 P04217P04217 Alpha-1B-glycoproteinAlpha-1B-glycoprotein A1BGA1BG 0.4560.456 3.56E-023.56E-02 P02787P02787 SerotransferrinSerotransferrin TFTF 0.4560.456 3.60E-023.60E-02 P08123P08123 Collagen alpha-2(I) chainCollagen alpha-2(I) chain COL1A2COL1A2 0.4610.461 3.95E-023.95E-02 P02790P02790 HemopexinHemopexin HPXHPX 0.4630.463 4.18E-024.18E-02

NIFTP에 유의미하게 높게 발현되는 169개 단백질169 proteins that are significantly highly expressed in NIFTP AccessionAccession ProteinNameProteinName GeneNameGeneName Fc:Fc:
(NIFTP)/(EFVPTC)(NIFTP)/(EFVPTC) Adj_P-Value:Adj_P-Value: P16278P16278 Beta-galactosidaseBeta-galactosidase GLB1GLB1 2.412.41 0.0438552730.043855273 P15291P15291 Beta-1,4-galactosyltransferase 1Beta-1,4-galactosyltransferase 1 B4GALT1B4GALT1 2.4262.426 0.0400971050.040097105 P02549P02549 Spectrin alpha chain, erythrocytic 1Spectrin alpha chain, erythrocytic 1 SPTA1SPTA1 2.4822.482 0.0420920290.042092029 P27487P27487 Dipeptidyl peptidase 4Dipeptidyl peptidase 4 DPP4DPP4 2.5112.511 0.0285453790.028545379 O75964O75964 ATP synthase subunit g, mitochondrialATP synthase subunit g, mitochondrial ATP5LATP5L 2.5222.522 0.0359348560.035934856 P24821P24821 TenascinTenascin TNCTNC 2.5542.554 0.0320221770.032022177 P43251-2P43251-2 Isoform 2 of BiotinidaseIsoform 2 of Biotinidase BTDBTD 2.5952.595 0.0289848490.028984849 P23381P23381 Tryptophan--tRNA ligase, cytoplasmicTryptophan--tRNA ligase, cytoplasmic WARSWARS 2.5962.596 0.0307109930.030710993 Q29963Q29963 HLA class I histocompatibility antigen, Cw-6 alpha chainHLA class I histocompatibility antigen, Cw-6 alpha chain HLA-CHLA-C 2.632.63 0.0240709990.024070999 P07919P07919 Cytochrome b-c1 complex subunit 6, mitochondrialCytochrome b-c1 complex subunit 6, mitochondrial UQCRHUQCRH 2.6892.689 0.0144443470.014444347 P07996P07996 Thrombospondin-1Thrombospondin-1 THBS1THBS1 2.6982.698 0.019134210.01913421 P26572P26572 Alpha-1,3-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferaseAlpha-1,3-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase MGAT1MGAT1 2.7222.722 0.0337178780.033717878 P12429P12429 Annexin A3Annexin A3 ANXA3ANXA3 2.8652.865 0.0097208610.009720861 P11277-2P11277-2 Isoform 2 of Spectrin beta chain, erythrocyticIsoform 2 of Spectrin beta chain, erythrocytic SPTBSPTB 2.8872.887 0.0062582750.006258275 P01892P01892 HLA class I histocompatibility antigen, A-2 alpha chainHLA class I histocompatibility antigen, A-2 alpha chain HLA-AHLA-A 2.9122.912 0.0080173190.008017319 P54802P54802 Alpha-N-acetylglucosaminidaseAlpha-N-acetylglucosaminidase NAGLUNAGLU 2.9682.968 0.0492082150.049208215 Q8WU39Q8WU39 Marginal zone B- and B1-cell-specific proteinMarginal zone B- and B1-cell-specific protein MZB1MZB1 3.0013.001 0.036903190.03690319 P13796P13796 Plastin-2Plastin-2 LCP1LCP1 3.0393.039 0.0070847350.007084735 Q96S96Q96S96 Phosphatidylethanolamine-binding protein 4Phosphatidylethanolamine-binding protein 4 PEBP4PEBP4 3.0423.042 0.0230147660.023014766 P02730P02730 Band 3 anion transport proteinBand 3 anion transport protein SLC4A1SLC4A1 3.0793.079 0.0042668960.004266896 P16157-14P16157-14 Isoform Er13 of Ankyrin-1Isoform Er13 of Ankyrin-1 ANK1ANK1 3.0973.097 0.0044512180.004451218 P03928P03928 ATP synthase protein 8ATP synthase protein 8 MT-ATP8MT-ATP8 3.1073.107 0.021224420.02122442 P17405P17405 Sphingomyelin phosphodiesteraseSphingomyelin phosphodiesterase SMPD1SMPD1 3.1093.109 0.0326659350.032665935 Q8IV08Q8IV08 Phospholipase D3Phospholipase D3 PLD3PLD3 3.133.13 0.0316426490.031642649 Q6UXG2Q6UXG2 UPF0577 protein KIAA1324UPF0577 protein KIAA1324 KIAA1324KIAA1324 3.1413.141 0.0162454370.016245437 P02743P02743 Serum amyloid P-componentSerum amyloid P-component APCSAPCS 3.163.16 0.0031243350.003124335 Q93073Q93073 Selenocysteine insertion sequence-binding protein 2-likeSelenocysteine insertion sequence-binding protein 2-like SECISBP2LSECISBP2L 3.1653.165 0.0030732810.003073281 P01877P01877 Immunoglobulin heavy constant alpha 2Immunoglobulin heavy constant alpha 2 IGHA2IGHA2 3.193.19 0.001532980.00153298 P01591P01591 Immunoglobulin J chainImmunoglobulin J chain JCHAINJCHAIN 3.2713.271 0.0134269670.013426967 P09917P09917 Arachidonate 5-lipoxygenaseArachidonate 5-lipoxygenase ALOX5ALOX5 3.293.29 0.0347120390.034712039 Q9BUN8Q9BUN8 Derlin-1Derlin-1 DERL1DERL1 3.2913.291 0.0286932960.028693296 O00391O00391 Sulfhydryl oxidase 1Sulfhydryl oxidase 1 QSOX1QSOX1 3.423.42 0.0038755650.003875565 P34897P34897 Serine hydroxymethyltransferase, mitochondrialSerine hydroxymethyltransferase, mitochondrial SHMT2SHMT2 3.4373.437 0.0010264910.001026491 P35556P35556 Fibrillin-2Fibrillin-2 FBN2FBN2 3.5543.554 0.0128383390.012838339 Q03518Q03518 Antigen peptide transporter 1Antigen peptide transporter 1 TAP1TAP1 3.7153.715 0.0041769950.004176995 Q99643Q99643 Succinate dehydrogenase cytochrome b560 subunit, mitochondrialSuccinate dehydrogenase cytochrome b560 subunit, mitochondrial SDHCSDHC 3.7463.746 0.0038997940.003899794 Q8NE62Q8NE62 Choline dehydrogenase, mitochondrialCholine dehydrogenase, mitochondrial CHDHCHDH 3.7633.763 0.0366121860.036612186 P05107P05107 Integrin beta-2Integrin beta-2 ITGB2ITGB2 3.8023.802 0.000653560.00065356 Q7Z7M0Q7Z7M0 Multiple epidermal growth factor-like domains protein 8Multiple epidermal growth factor-like domains protein 8 MEGF8MEGF8 3.913.91 0.0221022090.022102209 P23378P23378 Glycine dehydrogenase (decarboxylating), mitochondrialGlycine dehydrogenase (decarboxylating), mitochondrial GLDCGLDC 4.0024.002 0.0298913390.029891339 Q9BQ95Q9BQ95 Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrialEvolutionarily conserved signaling intermediate in Toll pathway, mitochondrial ECSITECSIT 4.0454.045 0.022844060.02284406 Q6UB35Q6UB35 Monofunctional C1-tetrahydrofolate synthase, mitochondrialMonofunctional C1-tetrahydrofolate synthase, mitochondrial MTHFD1LMTHFD1L 4.1544.154 0.0196893140.019689314 O43272O43272 Proline dehydrogenase 1, mitochondrialProline dehydrogenase 1, mitochondrial PRODHPRODH 4.3274.327 0.0032229640.003222964 O75636O75636 Ficolin-3Ficolin-3 FCN3FCN3 4.5464.546 0.0134269670.013426967 P08575P08575 Receptor-type tyrosine-protein phosphatase CReceptor-type tyrosine-protein phosphatase C PTPRCPTPRC 4.6294.629 7.95E-057.95E-05 Q6UX73Q6UX73 UPF0764 protein C16orf89UPF0764 protein C16orf89 C16orf89C16orf89 4.6794.679 3.32E-063.32E-06 P08519P08519 Apolipoprotein(a)Apolipoprotein(a) LPALPA 4.7214.721 3.06E-053.06E-05 P04233-2P04233-2 Isoform 2 of HLA class II histocompatibility antigen gamma chainIsoform 2 of HLA class II histocompatibility antigen gamma chain CD74CD74 4.7494.749 2.76E-062.76E-06 Q9Y5X9Q9Y5X9 Endothelial lipaseEndothelial lipase LIPGLIPG 4.8914.891 4.96E-064.96E-06 O00462O00462 Beta-mannosidaseBeta-mannosidase MANBAMANBA 4.9374.937 1.22E-051.22E-05 Q9BY50Q9BY50 Signal peptidase complex catalytic subunit SEC11CSignal peptidase complex catalytic subunit SEC11C SEC11CSEC11C 4.9714.971 0.0042597460.004259746 P61769P61769 Beta-2-microglobulinBeta-2-microglobulin B2MB2M 4.9824.982 2.98E-062.98E-06 Q4G0M1Q4G0M1 ErythroferroneErythroferrone ERFEERFE 4.9924.992 0.0050698910.005069891 P10412P10412 Histone H1.4Histone H1.4 HIST1H1EHIST1H1E 5.0395.039 2.44E-062.44E-06 Q9BZQ8Q9BZQ8 Protein NibanProtein Niban FAM129AFAM129A 5.0625.062 0.0039267190.003926719 P28330P28330 Long-chain specific acyl-CoA dehydrogenase, mitochondrialLong-chain specific acyl-CoA dehydrogenase, mitochondrial ACADLACADL 5.5065.506 0.0004464740.000446474 P20039P20039 HLA class II histocompatibility antigen, DRB1-11 beta chainHLA class II histocompatibility antigen, DRB1-11 beta chain HLA-DRB1HLA-DRB1 5.595.59 3.51E-073.51E-07 P30501P30501 HLA class I histocompatibility antigen, Cw-2 alpha chainHLA class I histocompatibility antigen, Cw-2 alpha chain HLA-CHLA-C 5.9025.902 0.000924980.00092498 O14498O14498 Immunoglobulin superfamily containing leucine-rich repeat proteinImmunoglobulin superfamily containing leucine-rich repeat protein ISLRISLR 6.1526.152 5.36E-085.36E-08 P01903P01903 HLA class II histocompatibility antigen, DR alpha chainHLA class II histocompatibility antigen, DR alpha chain HLA-DRAHLA-DRA 7.0397.039 3.15E-093.15E-09 Q9Y4X1-2Q9Y4X1-2 Isoform 2 of UDP-glucuronosyltransferase 2A1Isoform 2 of UDP-glucuronosyltransferase 2A1 UGT2A1UGT2A1 7.0397.039 9.68E-079.68E-07 P04233P04233 HLA class II histocompatibility antigen gamma chainHLA class II histocompatibility antigen gamma chain CD74CD74 7.1017.101 0.0002594980.000259498 P01911P01911 HLA class II histocompatibility antigen, DRB1-15 beta chainHLA class II histocompatibility antigen, DRB1-15 beta chain HLA-DRB1HLA-DRB1 7.4777.477 1.27E-071.27E-07 O75752O75752 UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 1UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 1 B3GALNT1B3GALNT1 8.2058.205 0.0003004120.000300412 Q6N022Q6N022 Teneurin-4Teneurin-4 TENM4TENM4 8.6458.645 0.0004679050.000467905 P28907P28907 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 CD38CD38 9.5019.501 1.54E-091.54E-09 P01909P01909 HLA class II histocompatibility antigen, DQ alpha 1 chainHLA class II histocompatibility antigen, DQ alpha 1 chain HLA-DQA1HLA-DQA1 9.6979.697 7.63E-067.63E-06 Q86WI1Q86WI1 Fibrocystin-LFibrocystin-L PKHD1L1PKHD1L1 11.09811.098 1.50E-141.50E-14 P20036P20036 HLA class II histocompatibility antigen, DP alpha 1 chainHLA class II histocompatibility antigen, DP alpha 1 chain HLA-DPA1HLA-DPA1 13.41513.415 3.35E-143.35E-14 P16190P16190 HLA class I histocompatibility antigen, A-33 alpha chainHLA class I histocompatibility antigen, A-33 alpha chain HLA-AHLA-A 16.66616.666 1.69E-161.69E-16 P56378-2P56378-2 Isoform 2 of 6.8 kDa mitochondrial proteolipidIsoform 2 of 6.8 kDa mitochondrial proteolipid MP68MP68 17.84317.843 4.83E-094.83E-09 P24310P24310 Cytochrome c oxidase subunit 7A1, mitochondrialCytochrome c oxidase subunit 7A1, mitochondrial COX7A1COX7A1 20.68520.685 1.69E-161.69E-16 O95678O95678 Keratin, type II cytoskeletal 75Keratin, type II cytoskeletal 75 KRT75KRT75 21.75521.755 1.69E-161.69E-16 P78540P78540 Arginase-2, mitochondrialArginase-2, mitochondrial ARG2ARG2 23.54523.545 1.69E-161.69E-16 P04440P04440 HLA class II histocompatibility antigen, DP beta 1 chainHLA class II histocompatibility antigen, DP beta 1 chain HLA-DPB1HLA-DPB1 34.06534.065 1.69E-161.69E-16 Q9NRK6Q9NRK6 ATP-binding cassette sub-family B member 10, mitochondrialATP-binding cassette sub-family B member 10, mitochondrial ABCB10ABCB10 10001000 1.69E-161.69E-16 Q99712Q99712 ATP-sensitive inward rectifier potassium channel 15ATP-sensitive inward rectifier potassium channel 15 KCNJ15KCNJ15 10001000 1.69E-161.69E-16 A6NE02A6NE02 BTB/POZ domain-containing protein 17BTB/POZ domain-containing protein 17 BTBD17BTBD17 10001000 1.69E-161.69E-16 Q8IZJ3Q8IZJ3 C3 and PZP-like alpha-2-macroglobulin domain-containing protein 8C3 and PZP-like alpha-2-macroglobulin domain-containing protein 8 CPAMD8CPAMD8 10001000 1.69E-161.69E-16 O75309O75309 Cadherin-16Cadherin-16 CDH16CDH16 10001000 1.69E-161.69E-16 Q7LFX5Q7LFX5 Carbohydrate sulfotransferase 15Carbohydrate sulfotransferase 15 CHST15CHST15 10001000 1.69E-161.69E-16 O95832O95832 Claudin-1Claudin-1 CLDN1CLDN1 10001000 1.69E-161.69E-16 P00742P00742 Coagulation factor XCoagulation factor X F10F10 10001000 1.69E-161.69E-16 Q07092Q07092 Collagen alpha-1(XVI) chainCollagen alpha-1(XVI) chain COL16A1COL16A1 10001000 1.69E-161.69E-16 P06681P06681 Complement C2Complement C2 C2C2 10001000 1.69E-161.69E-16 Q13616Q13616 Cullin-1Cullin-1 CUL1CUL1 10001000 1.69E-161.69E-16 P00395P00395 Cytochrome c oxidase subunit 1Cytochrome c oxidase subunit 1 MT-CO1MT-CO1 10001000 1.69E-161.69E-16 Q9HC16Q9HC16 DNA dC->dU-editing enzyme APOBEC-3GDNA dC->dU-editing enzyme APOBEC-3G APOBEC3GAPOBEC3G 10001000 1.69E-161.69E-16 P19387P19387 DNA-directed RNA polymerase II subunit RPB3DNA-directed RNA polymerase II subunit RPB3 POLR2CPOLR2C 10001000 1.69E-161.69E-16 Q5VTR2Q5VTR2 E3 ubiquitin-protein ligase BRE1AE3 ubiquitin-protein ligase BRE1A RNF20RNF20 10001000 1.69E-161.69E-16 P29323P29323 Ephrin type-B receptor 2Ephrin type-B receptor 2 EPHB2EPHB2 10001000 1.69E-161.69E-16 O60907O60907 F-box-like/WD repeat-containing protein TBL1XF-box-like/WD repeat-containing protein TBL1X TBL1XTBL1X 10001000 1.69E-161.69E-16 Q86UX7Q86UX7 Fermitin family homolog 3Fermitin family homolog 3 FERMT3FERMT3 10001000 1.69E-161.69E-16 P17302P17302 Gap junction alpha-1 proteinGap junction alpha-1 protein GJA1GJA1 10001000 1.69E-161.69E-16 Q9NZC3Q9NZC3 Glycerophosphodiester phosphodiesterase 1Glycerophosphodiester phosphodiesterase 1 GDE1GDE1 10001000 1.69E-161.69E-16 P49863P49863 Granzyme KGranzyme K GZMKGZMK 10001000 1.69E-161.69E-16 A4D1E9A4D1E9 GTP-binding protein 10GTP-binding protein 10 GTPBP10GTPBP10 10001000 1.69E-161.69E-16 Q15382Q15382 GTP-binding protein RhebGTP-binding protein Rheb RHEBRHEB 10001000 1.69E-161.69E-16 O95837O95837 Guanine nucleotide-binding protein subunit alpha-14Guanine nucleotide-binding protein subunit alpha-14 GNA14GNA14 10001000 1.69E-161.69E-16 O95251O95251 Histone acetyltransferase KAT7Histone acetyltransferase KAT7 KAT7KAT7 10001000 1.69E-161.69E-16 P13747P13747 HLA class I histocompatibility antigen, alpha chain EHLA class I histocompatibility antigen, alpha chain E HLA-EHLA-E 10001000 1.69E-161.69E-16 P30486P30486 HLA class I histocompatibility antigen, B-48 alpha chainHLA class I histocompatibility antigen, B-48 alpha chain HLA-BHLA-B 10001000 1.69E-161.69E-16 Q9NVR2Q9NVR2 Integrator complex subunit 10Integrator complex subunit 10 INTS10INTS10 10001000 1.69E-161.69E-16 P13612P13612 Integrin alpha-4Integrin alpha-4 ITGA4ITGA4 10001000 1.69E-161.69E-16 P20702P20702 Integrin alpha-XIntegrin alpha-X ITGAXITGAX 10001000 1.69E-161.69E-16 Q8TB37Q8TB37 Iron-sulfur protein NUBPLIron-sulfur protein NUBPL NUBPLNUBPL 10001000 1.69E-161.69E-16 Q13951-2Q13951-2 Isoform 2 of Core-binding factor subunit betaIsoform 2 of Core-binding factor subunit beta CBFBCBFB 10001000 1.69E-161.69E-16 Q92629-2Q92629-2 Isoform 2 of Delta-sarcoglycanIsoform 2 of Delta-sarcoglycan SGCDSGCD 10001000 1.69E-161.69E-16 Q9NYP7-2Q9NYP7-2 Isoform 2 of Elongation of very long chain fatty acids protein 5Isoform 2 of Elongation of very long chain fatty acids protein 5 ELOVL5ELOVL5 10001000 1.69E-161.69E-16 Q8N4Q1-2Q8N4Q1-2 Isoform 2 of Mitochondrial intermembrane space import and assembly protein 40Isoform 2 of Mitochondrial intermembrane space import and assembly protein 40 CHCHD4CHCHD4 10001000 1.69E-161.69E-16 P15941-2P15941-2 Isoform 2 of Mucin-1Isoform 2 of Mucin-1 MUC1MUC1 10001000 1.69E-161.69E-16 Q3MHD2-2Q3MHD2-2 Isoform 2 of Protein LSM12 homologIsoform 2 of Protein LSM12 homolog LSM12LSM12 10001000 1.69E-161.69E-16 Q9Y2D2-2Q9Y2D2-2 Isoform 2 of UDP-N-acetylglucosamine transporterIsoform 2 of UDP-N-acetylglucosamine transporter SLC35A3SLC35A3 10001000 1.69E-161.69E-16 Q9Y2I8-2Q9Y2I8-2 Isoform 2 of WD repeat-containing protein 37Isoform 2 of WD repeat-containing protein 37 WDR37WDR37 10001000 1.69E-161.69E-16 O95258-3O95258-3 Isoform 3 of Brain mitochondrial carrier protein 1Isoform 3 of Brain mitochondrial carrier protein 1 SLC25A14SLC25A14 10001000 1.69E-161.69E-16 P33241-3P33241-3 Isoform 3 of Lymphocyte-specific protein 1Isoform 3 of Lymphocyte-specific protein 1 LSP1LSP1 10001000 1.69E-161.69E-16 Q9NPH3-5Q9NPH3-5 Isoform 4 of Interleukin-1 receptor accessory proteinIsoform 4 of Interleukin-1 receptor accessory protein IL1RAPIL1RAP 10001000 1.69E-161.69E-16 P98194-7P98194-7 Isoform 7 of Calcium-transporting ATPase type 2C member 1Isoform 7 of Calcium-transporting ATPase type 2C member 1 ATP2C1ATP2C1 10001000 1.69E-161.69E-16 O00338-2O00338-2 Isoform Long of Sulfotransferase 1C2Isoform Long of Sulfotransferase 1C2 SULT1C2SULT1C2 10001000 1.69E-161.69E-16 Q14525Q14525 Keratin, type I cuticular Ha3-IIKeratin, type I cuticular Ha3-II KRT33BKRT33B 10001000 1.69E-161.69E-16 O76013O76013 Keratin, type I cuticular Ha6Keratin, type I cuticular Ha6 KRT36KRT36 10001000 1.69E-161.69E-16 Q9NSB2Q9NSB2 Keratin, type II cuticular Hb4Keratin, type II cuticular Hb4 KRT84KRT84 10001000 1.69E-161.69E-16 P78386P78386 Keratin, type II cuticular Hb5Keratin, type II cuticular Hb5 KRT85KRT85 10001000 1.69E-161.69E-16 Q6ZUX7Q6ZUX7 Lipoma HMGIC fusion partner-like 2 proteinLipoma HMGIC fusion partner-like 2 protein LHFPL2LHFPL2 10001000 1.69E-161.69E-16 Q6PCB7Q6PCB7 Long-chain fatty acid transport protein 1Long-chain fatty acid transport protein 1 SLC27A1SLC27A1 10001000 1.69E-161.69E-16 Q5K4L6Q5K4L6 Long-chain fatty acid transport protein 3Long-chain fatty acid transport protein 3 SLC27A3SLC27A3 10001000 1.69E-161.69E-16 P38571P38571 Lysosomal acid lipase/cholesteryl ester hydrolaseLysosomal acid lipase/cholesteryl ester hydrolase LIPALIPA 10001000 1.69E-161.69E-16 Q9UBB5Q9UBB5 Methyl-CpG-binding domain protein 2Methyl-CpG-binding domain protein 2 MBD2MBD2 10001000 1.69E-161.69E-16 Q15800Q15800 Methylsterol monooxygenase 1Methylsterol monooxygenase 1 MSMO1MSMO1 10001000 1.69E-161.69E-16 Q5TGZ0Q5TGZ0 MICOS complex subunit MIC10MICOS complex subunit MIC10 MINOS1MINOS1 10001000 1.69E-161.69E-16 Q86VD7Q86VD7 Mitochondrial coenzyme A transporter SLC25A42Mitochondrial coenzyme A transporter SLC25A42 SLC25A42SLC25A42 10001000 1.69E-161.69E-16 Q9BT17Q9BT17 Mitochondrial ribosome-associated GTPase 1Mitochondrial ribosome-associated GTPase 1 MTG1MTG1 10001000 1.69E-161.69E-16 Q8IWA4Q8IWA4 Mitofusin-1Mitofusin-1 MFN1MFN1 10001000 1.69E-161.69E-16 Q9BV23Q9BV23 Monoacylglycerol lipase ABHD6Monoacylglycerol lipase ABHD6 ABHD6ABHD6 10001000 1.69E-161.69E-16 Q68D85Q68D85 Natural cytotoxicity triggering receptor 3 ligand 1Natural cytotoxicity triggering receptor 3 ligand 1 NCR3LG1NCR3LG1 10001000 1.69E-161.69E-16 Q8IXH7Q8IXH7 Negative elongation factor C/DNegative elongation factor C/D NELFCDNELFCD 10001000 1.69E-161.69E-16 P08246P08246 Neutrophil elastaseNeutrophil elastase ELANEELANE 10001000 1.69E-161.69E-16 Q5SRE5Q5SRE5 Nucleoporin NUP188 homologNucleoporin NUP188 homolog NUP188NUP188 10001000 1.69E-161.69E-16 Q7Z412Q7Z412 Peroxisome assembly protein 26Peroxisome assembly protein 26 PEX26PEX26 10001000 1.69E-161.69E-16 Q8WUK0Q8WUK0 Phosphatidylglycerophosphatase and protein-tyrosine phosphatase 1Phosphatidylglycerophosphatase and protein-tyrosine phosphatase 1 PTPMT1PTPMT1 10001000 1.69E-161.69E-16 O60831O60831 PRA1 family protein 2PRA1 family protein 2 PRAF2PRAF2 10001000 1.69E-161.69E-16 Q9H300Q9H300 Presenilins-associated rhomboid-like protein, mitochondrialPresenilins-associated rhomboid-like protein, mitochondrial PARLPARL 10001000 1.69E-161.69E-16 Q8N4Q0Q8N4Q0 Prostaglandin reductase 3Prostaglandin reductase 3 ZADH2ZADH2 10001000 1.69E-161.69E-16 O00622O00622 Protein CYR61Protein CYR61 CYR61CYR61 10001000 1.69E-161.69E-16 Q8N5M9Q8N5M9 Protein jagunal homolog 1Protein jagunal homolog 1 JAGN1JAGN1 10001000 1.69E-161.69E-16 Q53HC9Q53HC9 Protein TSSC1Protein TSSC1 EIPR1EIPR1 10001000 1.69E-161.69E-16 Q2TB90Q2TB90 Putative hexokinase HKDC1Putative hexokinase HKDC1 HKDC1HKDC1 10001000 1.69E-161.69E-16 Q8N2H3Q8N2H3 Pyridine nucleotide-disulfide oxidoreductase domain-containing protein 2Pyridine nucleotide-disulfide oxidoreductase domain-containing protein 2 PYROXD2PYROXD2 10001000 1.69E-161.69E-16 Q6ZRI8Q6ZRI8 Rho GTPase-activating protein 36Rho GTPase-activating protein 36 ARHGAP36ARHGAP36 10001000 1.69E-161.69E-16 Q92541Q92541 RNA polymerase-associated protein RTF1 homologRNA polymerase-associated protein RTF1 homolog RTF1RTF1 10001000 1.69E-161.69E-16 Q9NRX1Q9NRX1 RNA-binding protein PNO1RNA-binding protein PNO1 PNO1PNO1 10001000 1.69E-161.69E-16 P83110P83110 Serine protease HTRA3Serine protease HTRA3 HTRA3HTRA3 10001000 1.69E-161.69E-16 Q9H788Q9H788 SH2 domain-containing protein 4ASH2 domain-containing protein 4A SH2D4ASH2D4A 10001000 1.69E-161.69E-16 O95436O95436 Sodium-dependent phosphate transport protein 2BSodium-dependent phosphate transport protein 2B SLC34A2SLC34A2 10001000 1.69E-161.69E-16 Q8N3V7Q8N3V7 SynaptopodinSynaptopodin SYNPOSYNPO 10001000 1.69E-161.69E-16 Q9NPA8Q9NPA8 Transcription and mRNA export factor ENY2Transcription and mRNA export factor ENY2 ENY2ENY2 10001000 1.69E-161.69E-16 Q12788Q12788 Transducin beta-like protein 3Transducin beta-like protein 3 TBL3TBL3 10001000 1.69E-161.69E-16 Q9H061Q9H061 Transmembrane protein 126ATransmembrane protein 126A TMEM126ATMEM126A 10001000 1.69E-161.69E-16 Q8N3G9Q8N3G9 Transmembrane protein 130Transmembrane protein 130 TMEM130TMEM130 10001000 1.69E-161.69E-16 Q9BUB7Q9BUB7 Transmembrane protein 70, mitochondrialTransmembrane protein 70, mitochondrial TMEM70TMEM70 10001000 1.69E-161.69E-16 P30530P30530 Tyrosine-protein kinase receptor UFOTyrosine-protein kinase receptor UFO AXLAXL 10001000 1.69E-161.69E-16 Q9GZZ9Q9GZZ9 Ubiquitin-like modifier-activating enzyme 5Ubiquitin-like modifier-activating enzyme 5 UBA5UBA5 10001000 1.69E-161.69E-16 Q14376Q14376 UDP-glucose 4-epimeraseUDP-glucose 4-epimerase GALEGALE 10001000 1.69E-161.69E-16 O15294O15294 UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunitUDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit OGTOGT 10001000 1.69E-161.69E-16 B0I1T2B0I1T2 Unconventional myosin-IgUnconventional myosin-Ig MYO1GMYO1G 10001000 1.69E-161.69E-16 Q4G0F5Q4G0F5 Vacuolar protein sorting-associated protein 26BVacuolar protein sorting-associated protein 26B VPS26BVPS26B 10001000 1.69E-161.69E-16 Q9BZH6Q9BZH6 WD repeat-containing protein 11WD repeat-containing protein 11 WDR11WDR11 10001000 1.69E-161.69E-16 Q8IWA0Q8IWA0 WD repeat-containing protein 75WD repeat-containing protein 75 WDR75WDR75 10001000 1.69E-161.69E-16 Q9H0D2Q9H0D2 Zinc finger protein 541Zinc finger protein 541 ZNF541ZNF541 10001000 1.69E-161.69E-16

상기에서 살펴본 바와 같이, 침윤성 EFVPTC와 NIFTP를 구분하기 위하여 상기 표에 나타난 단백질(들)을 이용할 수 있다. 아울러 본 발명자가 제공하는 키트로 제작되어 환자 샘플로부터 갑상선암 수술 진행 여부와 수술 범위를 빠르게 검토함에 이용될 수 있을 것으로 기대된다.As described above, the protein(s) shown in the table may be used to distinguish invasive EFVPTC and NIFTP. In addition, it is expected that the kits provided by the present inventors can be used to quickly review the progression of thyroid cancer surgery and the surgical range from patient samples.

실시예 2. 차별 발현되는 단백질의 생물학적 의미 파악Example 2. Identification of biological significance of differentially expressed proteins

2개의 조직에서 차별되게 발현되는 단백질 리스트를 이용하여 생물학적 의미를 파악하기 위해서 ClueGo 프로그램을 통해서 GO 분석을 수행하였다.GO analysis was performed through the ClueGo program in order to grasp the biological significance using a protein list that is differentially expressed in two tissues.

먼저, NIFTP에서 유의미하게 증가하는 단백질은 아래와 같은 특징을 가지는 것으로 확인되었다.First, it was confirmed that the protein significantly increased in NIFTP has the following characteristics.

▷ 세포질 성분(Cellular component)▷ Cellular component

- MHC 단백질 복합체(MHC protein complex), 소포체 망막의 내강 측(lumenal side of endoplasmic reticulum membrane), 소포체 막의 루멘 측의 필수 구성 요소(integral component of lumenal side of endoplasmic reticulum membrane), 소포체에서 골지로의 운반 소포막(ER to Golgi transport vesicle membrane), COPII 코팅된 소포체에서 골지 수송 소포(COPII-coated ER to Golgi transport vesicle), 클라트린-코팅된 세포 내 소포막(clathrin-coated endocytic vesicle membrane), 골지 관련 소포막(Golgi-associated vesicle membrane)에 존재함. -MHC protein complex, lumenal side of endoplasmic reticulum membrane, integral component of lumenal side of endoplasmic reticulum membrane, transport from endoplasmic reticulum to Golgi ER to Golgi transport vesicle membrane, COPII-coated ER to Golgi transport vesicle, clathrin-coated endocytic vesicle membrane, Golgi related Present in the vesicle membrane (Golgi-associated vesicle membrane).

- MHC complex 관련 단백질과 소포체(ER) 및 골지(Golgi) 부근에서 단백질들의 발현양이 증가함(표 5 참조). -MHC complex-related proteins and expression levels of proteins increased in the vicinity of the endoplasmic reticulum (ER) and Golgi (see Table 5).

Figure pat00051
Figure pat00051

▷ 분자적 기능(Molecular function)▷ Molecular function

- MHC 관련 분자기작이 대부분을 차지함. TAP 바인딩, 펩티드 항원 결합, MHC 단백질 복합체 결합, MHC 클래스 II 수용체 활성, 피브로넥틴 결합. (표 6 참조)-MHC-related molecular mechanisms dominated the majority. TAP binding, peptide antigen binding, MHC protein complex binding, MHC class II receptor activity, fibronectin binding. (See Table 6)

Figure pat00052
Figure pat00052

▷ 생물학적 과정▷ Biological process

T 세포 매개 세포 독성, 신장 여과, 숙주 세포로의 바이러스 진입 조절, T 세포 매개 세포 독성의 조절, 단핵구 분화의 조절, 알파-베타 T 세포 증식의 조절, 단백질 이종사량체화(protein heterotetramerization), 자연 살해 세포 매개 세포 독성으로부터의 보호, T 세포 매개 면역의 양성 조절, T 세포 매개 세포 독성의 양성 조절,인지질 이화 과정, 자연 살해 세포 매개 면역 또는 세포 독성의 음성 조절, 백혈구 매개 세포 독성의 음성 조절, 세포 사멸의 음성 조절, 인터페론 감마 메개 신호 전달 경로, 인테그린 활성화, 히스톤 H3-K4 트리메틸화, 사구체 여과, 갈락토오스 대사 과정, 다른 유기체의 검출, 외부 바이오틱 자극의 검출, 바이오틱 자극의 검출, 박테리아의 검출, 아팝토시스 세포 제거, MHC 클래스 I을 통한 외인성 펩티드 항원의 항원 가공 및 제시, TAP-독립적, 내인성 펩티드 항원의 항원 처리 및 제시, 항균성 체액 반응, 알파-베타 T 세포 증식(alpha-beta T cell proliferation)(표 7 참조).T cell mediated cytotoxicity, kidney filtration, regulation of viral entry into host cells, regulation of T cell mediated cytotoxicity, regulation of monocyte differentiation, regulation of alpha-beta T cell proliferation, protein heterotetramerization, natural killing Protection from cytotoxicity, positive regulation of T cell mediated immunity, positive regulation of T cell mediated cytotoxicity, phospholipid catabolism process, negative regulation of natural killer cell mediated immunity or cytotoxicity, negative regulation of leukocyte mediated cytotoxicity, cell Negative regulation of death, interferon gamma-mediated signaling pathway, integrin activation, histone H3-K4 trimethylation, glomerular filtration, galactose metabolism, detection of other organisms, detection of external biotic stimuli, detection of biotic stimuli, detection of bacteria , Apoptotic cell removal, antigen processing and presentation of exogenous peptide antigens through MHC class I, antigen processing and presentation of TAP-independent, endogenous peptide antigens, antimicrobial humoral response, alpha-beta T cell proliferation (alpha-beta T cell proliferation) (see Table 7).

Figure pat00053
Figure pat00053

또한, 침윤성 EFVPTC에서 유의미하게 증가하는 단백질은 아래와 같은 특징을 가지는 것으로 확인되었다.In addition, it was confirmed that the protein significantly increased in the invasive EFVPTC has the following characteristics.

▷ 세포질 성분(Cellular component)▷ Cellular component

- 혈액 미세 입자, 혈소판 알파 과립, 혈소판 알파 과립 루멘(platelet alpha granule lumen), 수포체(multivesicular body), GTPase 복합체, 이종삼량체 G- 단백질 복합체, 이차 리소좀, 오토리소좀(autolysosome)에 존재함. -Present in blood microparticles, platelet alpha granules, platelet alpha granule lumen, multivesicular body, GTPase complex, heterotrimeric G-protein complex, secondary lysosome, and autolysosome.

MHC complex 관련단백질과 소포체(ER) 및 골지(Golgi) 부근에서 단백질들의 발현량이 증가함(표 8 참조).MHC complex-related proteins and expression levels of proteins increased in the endoplasmic reticulum (ER) and the vicinity of Golgi (see Table 8).

Figure pat00054
Figure pat00054

▷ 분자적 기능(Molecular function)▷ Molecular function

- 구리 이온 결합-Copper ion bonding

Figure pat00055
Figure pat00055

▷ 생물학적 과정▷ Biological process

- 과당 6-인산 대사 과정(fructose 6-phosphate metabolic process), 인테그린-매개 신호 전달 경로의 조절(regulation of integrin-mediated signaling pathway), 고밀도 지단백질 입자 리모델링(high-density lipoprotein particle remodeling), 신경 줄기 세포 집단 유지(neuronal stem cell population maintenance), Rho 단백질 신호 전달의 양성 조절(positive regulation of Rho protein signal transduction), 급성기 반응(acute-phase response), 나트륨 독립적 유기 음이온 수송(sodium-independent organic anion transport), 액틴 필라멘트 번들 어셈블리의 양성 조절(positive regulation of actin filament bundle assembly), 거대 분자 복합 리모델링(macromolecular complex remodeling), 혈장 지단백질 입자 리모델링(plasma lipoprotein particle remodeling), 단백질 지질 복합 리모델링(protein-lipid complex remodeling), Ras 단백질 신호 전달의 양성 조절(positive regulation of Ras protein signal transduction), 스트레스 섬유 어셈블리의 양성 조절(positive regulation of stress fiber assembly), 혈소판 탈과립(platelet degranulation), 증가된 산소 수준에 대한 반응(response to increased oxygen levels), 바이러스에 의한 바이러스에 대한 방어 반응의 조절(regulation of defense response to virus by virus), GTPase 활성의 음성 조절(negative regulation of GTPase activity), 음이온 항상성(canonical glycolysis), 작은 GTPase 매개 신호 전달의 양성 조절(positive regulation of small GTPase mediated signal transduction), 표준 당분해(canonical glycolysis), 피루브산에 대한 포도당 이화 과정(glucose catabolic process to pyruvate), NADH 재생(NADH regeneration), 트리글리세리드 이화 과정(triglyceride catabolic process), 포도당-6-인산을 통한 해당과정(glycolytic process through glucose-6-phosphate), 과당-6-인산을 통한 해당 과정(glycolytic process through fructose-6-phosphate)(표 10 참조).-Fructose 6-phosphate metabolic process, regulation of integrin-mediated signaling pathway, high-density lipoprotein particle remodeling, neural stem cells Neuronal stem cell population maintenance, positive regulation of Rho protein signal transduction, acute-phase response, sodium-independent organic anion transport, Positive regulation of actin filament bundle assembly, macromolecular complex remodeling, plasma lipoprotein particle remodeling, protein-lipid complex remodeling, Positive regulation of Ras protein signal transduction, positive regulation of stress fiber assembly, platelet degranulation, response to increased oxygen levels oxygen levels), regulation of defense response to virus by virus, negative regulation of GTPase activity gulation of GTPase activity, canonical glycolysis, positive regulation of small GTPase mediated signal transduction, canonical glycolysis, glucose catabolic process for pyruvate to pyruvate), NADH regeneration, triglyceride catabolic process, glycolytic process through glucose-6-phosphate, glycolytic process through glucose-6-phosphate ( glycolytic process through fructose-6-phosphate) (see Table 10).

Figure pat00056
Figure pat00056

또한, 도 7에 나타난 바와 같이, GO분석을 통해 NIFTP는 면역반응과 관련된 단백질이 상대적으로 높게 발현되며 침윤성 EFVPTC의 경우는 warburg effect와 관련 기작이 활성화되는 것을 확인하였다.In addition, as shown in FIG. 7, it was confirmed that the protein related to the immune response was relatively high in NIFTP through GO analysis, and that the warburg effect and related mechanisms were activated in the case of invasive EFVPTC.

실시예 3. 최종 마커 단백질 선택Example 3. Final Marker Protein Selection

도 8에 도시된 workflow에 따라, 표 1 내지 표 4에 기재된 단백질 중에서 유의미한 마커를 선별하였다.According to the workflow shown in Fig. 8, significant markers were selected among the proteins shown in Tables 1 to 4.

구체적으로, 상기 실시예 1 및 2에 따라 침윤성 EFVPTC 시료군 및 NIFTP 시료군에서만 검출되는 단백질 마커를 도출하였으며, p value가 0.05 미만이면서, 단백질의 펩타이드 count 수가 2 이상이고, 유전자 온톨로지(gene ontology) 결과 다음 범주에 하나 이상 해당되는 단백질을 분리하였다 : ①세포외 엑소좀에 존재, ②세포막에 존재, ③세포 표면에 존재, ④플라즈마 단백질체 데이터베이스에 등록.Specifically, protein markers detected only in the invasive EFVPTC sample group and the NIFTP sample group were derived according to Examples 1 and 2, and the p value was less than 0.05, the number of peptide counts of the protein was 2 or more, and gene ontology. Results One or more proteins that fall under the following categories were isolated: ① present in extracellular exosomes, ② present in cell membranes, ③ present on the cell surface, ④ registered in the plasma protein body database.

그 결과, 최종 마커로 선택된 단백질체를 하기 표 11 및 표 12에 기재하였다.As a result, the protein bodies selected as the final markers are shown in Tables 11 and 12 below.

NIFTP에 유의미하게 높게 발현되는 단백질Proteins that are significantly high in NIFTP Accession Accession Protein nameProtein name AbundanceAbundance # Peptides# Peptides Celluar CompartmentCelluar Compartment Plasma proteome databasePlasma proteome database P13747P13747 HLA class I histocompatibility antigen, alpha chain EHLA class I histocompatibility antigen, alpha chain E 6625008.8436625008.843 55 extracellular exosome, membraneextracellular exosome, membrane HPRD_00877HPRD_00877 Q9NSB2Q9NSB2 Keratin, type II cuticular Hb4Keratin, type II cuticular Hb4 256141.7786256141.7786 44 extracellular exosomeextracellular exosome HPRD_09098HPRD_09098 Q14525Q14525 Keratin, type I cuticular Ha3-IIKeratin, type I cuticular Ha3-II 12418371.312418371.3 44 membranemembrane HPRD_04136HPRD_04136 P13612P13612 Integrin alpha-4Integrin alpha-4 739568.6997739568.6997 33 extracellular exosomeextracellular exosome HPRD_01894HPRD_01894 Q5SRE5Q5SRE5 Nucleoporin NUP188 homologNucleoporin NUP188 homolog 356916.3218356916.3218 1One extracellular exosomeextracellular exosome HPRD_18582HPRD_18582 Q9BZH6Q9BZH6 WD repeat-containing protein 11WD repeat-containing protein 11 319888.7467319888.7467 1One membranemembrane HPRD_16218HPRD_16218 Q8IXH7Q8IXH7 Negative elongation factor C/DNegative elongation factor C/D 1133431.011133431.01 1One extracellular exosomeextracellular exosome HPRD_16096HPRD_16096 Q9NYP7Q9NYP7 Isoform 2 of Elongation of very long chain fatty acids protein 5Isoform 2 of Elongation of very long chain fatty acids protein 5 807066.2489807066.2489 1One extracellular exosomeextracellular exosome HPRD_13268HPRD_13268 O75309O75309 Cadherin-16Cadherin-16 326339.7002326339.7002 1One extracellular exosomeextracellular exosome HPRD_11929HPRD_11929 P06681P06681 Complement C2Complement C2 962996.0995962996.0995 1One extracellular exosomeextracellular exosome HPRD_08939HPRD_08939 Q86UX7Q86UX7 Fermitin family homolog 3Fermitin family homolog 3 672995.3977672995.3977 1One extracellular exosome, membraneextracellular exosome, membrane HPRD_07440HPRD_07440 O76013O76013 Keratin, type I cuticular Ha6Keratin, type I cuticular Ha6 6384383.2456384383.245 1One extracellular exosomeextracellular exosome HPRD_05174HPRD_05174 Q9NPH3Q9NPH3 Isoform 4 of Interleukin-1 receptor accessory proteinIsoform 4 of Interleukin-1 receptor accessory protein 1800895.3581800895.358 1One extracellular exosomeextracellular exosome HPRD_04021HPRD_04021 O00338O00338 Isoform Long of Sulfotransferase 1C2Isoform Long of Sulfotransferase 1C2 249463.4872249463.4872 1One extracellular exosomeextracellular exosome HPRD_03858HPRD_03858 Q99712Q99712 ATP-sensitive inward rectifier potassium channel 15ATP-sensitive inward rectifier potassium channel 15 311000.9826311000.9826 1One extracellular exosomeextracellular exosome HPRD_03659HPRD_03659 Q15382Q15382 GTP-binding protein RhebGTP-binding protein Rheb 748327.0861748327.0861 1One extracellular exosomeextracellular exosome HPRD_03188HPRD_03188 P15941P15941 Isoform 2 of Mucin-1Isoform 2 of Mucin-1 1667789.0931667789.093 1One extracellular exosomeextracellular exosome HPRD_01152HPRD_01152 P33241P33241 Isoform 3 of Lymphocyte-specific protein 1Isoform 3 of Lymphocyte-specific protein 1 441449.1374441449.1374 1One extracellular exosome, membraneextracellular exosome, membrane HPRD_01083HPRD_01083 P20702P20702 Integrin alpha-XIntegrin alpha-X 250525.7256250525.7256 1One extracellular exosomeextracellular exosome HPRD_01051HPRD_01051 P08246P08246 Neutrophil elastaseNeutrophil elastase 185458.3693185458.3693 1One extracellular exosome, membraneextracellular exosome, membrane HPRD_00554HPRD_00554 Q13951Q13951 Isoform 2 of Core-binding factor subunit betaIsoform 2 of Core-binding factor subunit beta 375101.0991375101.0991 1One extracellular exosomeextracellular exosome HPRD_00418HPRD_00418 P30530P30530 Tyrosine-protein kinase receptor UFOTyrosine-protein kinase receptor UFO 549536.1945549536.1945 1One extracellular exosome, membraneextracellular exosome, membrane HPRD_00171HPRD_00171

침윤성 EFVPTC에 유의미하게 높게 발현되는 단백질Protein that is significantly high in invasive EFVPTC Accession Accession Protein nameProtein name AbundanceAbundance # Peptides# Peptides Celluar CompartmentCelluar Compartment Plasma proteome databasePlasma proteome database Q96QR1Q96QR1 Secretoglobin family 3A member 1Secretoglobin family 3A member 1 5849636.5355849636.535 3232 extracellular exosomeextracellular exosome HPRD_05932HPRD_05932 P05413P05413 Fatty acid-binding protein, heartFatty acid-binding protein, heart 6765365.2466765365.246 2121 extracellular exosomeextracellular exosome HPRD_00613HPRD_00613 P07998P07998 Ribonuclease pancreaticRibonuclease pancreatic 773105.639773105.639 1313 extracellular exosomeextracellular exosome HPRD_01591HPRD_01591 P03950P03950 AngiogeninAngiogenin 438181.128438181.128 99 extracellular exosomeextracellular exosome HPRD_00105HPRD_00105 Q9BRF8Q9BRF8 Serine/threonine-protein phosphatase CPPED1Serine/threonine-protein phosphatase CPPED1 449476.036449476.036 55 extracellular exosomeextracellular exosome HPRD_07735HPRD_07735 Q9BZV1Q9BZV1 UBX domain-containing protein 6UBX domain-containing protein 6 272971.764272971.764 55 extracellular exosomeextracellular exosome HPRD_18253HPRD_18253 O14964O14964 Hepatocyte growth factor-regulated tyrosine kinase substrateHepatocyte growth factor-regulated tyrosine kinase substrate 3279125.3783279125.378 33 extracellular exosomeextracellular exosome HPRD_05085HPRD_05085 O00757O00757 Fructose-1,6-bisphosphatase isozyme 2Fructose-1,6-bisphosphatase isozyme 2 2006825.5202006825.520 33 extracellular exosomeextracellular exosome HPRD_04322HPRD_04322 Q99962Q99962 Endophilin-A1Endophilin-A1 863853.742863853.742 33 extracellular exosomeextracellular exosome HPRD_05125HPRD_05125 Q8TB96Q8TB96 T-cell immunomodulatory proteinT-cell immunomodulatory protein 1163150.4141163150.414 22 extracellular exosomeextracellular exosome HPRD_16692HPRD_16692 Q8IZA0Q8IZA0 Dyslexia-associated protein KIAA0319-like proteinDyslexia-associated protein KIAA0319-like protein 333361.447333361.447 22 extracellular exosomeextracellular exosome HPRD_11164HPRD_11164 P25940P25940 Collagen alpha-3(V) chainCollagen alpha-3(V) chain 763118.892763118.892 1One extracellular exosomeextracellular exosome HPRD_00369HPRD_00369

이상의 실시예를 종합하여, 본 발명자들은 상기한 본 발명의 단백질 마커를 이용하여 침윤성 EFVPTC와 NIFTP를 구분할 수 있어, 기존에 유전학적으로 구별이 어려웠던 악성 종양과 경계성 종양을 구분함으로써 수술이 꼭 필요한 침윤성 EFVPTC를 보다 정확히 진단할 수 있을 것으로 기대된다. 따라서, 본 발명은 상기한 본 발명의 단백질을 검출하는 제제를 유효성분으로 포함하는 침윤성 EFVPTC와 NIFTP 구분용 조성물, 구분 방법 및 구분용 키트를 제공할 수 있을 것으로 기대된다.In summarizing the above examples, the present inventors can distinguish between invasive EFVPTC and NIFTP using the protein marker of the present invention, so that surgery is essential by distinguishing between malignant tumors and borderline tumors, which were previously difficult to distinguish genetically. It is expected that invasive EFVPTC can be diagnosed more accurately. Therefore, the present invention is expected to be able to provide a composition for distinguishing invasive EFVPTC and NIFTP, a method for distinguishing, and a kit for classification, including the agent for detecting the protein of the present invention as an active ingredient.

전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The above description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains will be able to understand that other specific forms can be easily modified without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative and non-limiting in all respects.

Claims (12)

하기 표 11 및 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제를 유효성분으로 포함하는 침윤성 피막형 여포 변이 갑상선 유두암(EFVPTC, Encapsulated FVPTC)과 유두암종유사핵모양비침습소포종양(NIFTP)의 분류용 조성물.
[표 11]
Figure pat00057

[표 12]
Figure pat00058

Infiltrating capsular follicular mutant thyroid papillary cancer (EFVPTC, Encapsulated FVPTC) and papillary carcinoma-like nuclei comprising as an active ingredient an agent for measuring the expression level of one or more proteins selected from the group consisting of the proteins listed in Table 11 and Table 12 below or mRNA expression level thereof. Composition for classification of non-invasive vesicle tumors (NIFTP).
[Table 11]
Figure pat00057

[Table 12]
Figure pat00058

 제1항에 있어서,
상기 조성물은 하기 표 13 및 표 14에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제를 더 포함하는 것을 특징으로 하는, 조성물.
[표 13]
Figure pat00059

Figure pat00060

Figure pat00061

Figure pat00062

Figure pat00063

[표 14]
Figure pat00064

Figure pat00065

Figure pat00066

Figure pat00067

Figure pat00068

Figure pat00069

Figure pat00070

Figure pat00071

Figure pat00072

Figure pat00073

Figure pat00074

Figure pat00075

Figure pat00076

Figure pat00077

Figure pat00078

Figure pat00079

Figure pat00080

The method of claim 1,
The composition further comprises an agent for measuring the mRNA expression level of one or more proteins selected from the group consisting of the proteins shown in Table 13 and Table 14 below.
[Table 13]
Figure pat00059

Figure pat00060

Figure pat00061

Figure pat00062

Figure pat00063

[Table 14]
Figure pat00064

Figure pat00065

Figure pat00066

Figure pat00067

Figure pat00068

Figure pat00069

Figure pat00070

Figure pat00071

Figure pat00072

Figure pat00073

Figure pat00074

Figure pat00075

Figure pat00076

Figure pat00077

Figure pat00078

Figure pat00079

Figure pat00080

 제1항에 있어서,
상기 mRNA의 발현 수준을 측정하는 제제는 상기 mRNA에 특이적으로 결합하는 프로브 또는 프라이머인 것을 특징으로 하는, 조성물.
The method of claim 1,
The composition for measuring the expression level of the mRNA is characterized in that the probe or primer specifically binding to the mRNA.
 제1항에 있어서,
상기 단백질의 발현 수준을 측정하는 제제는 상기 단백질에 특이적인 항체 또는 앱타머인 것을 특징으로 하는, 조성물.
The method of claim 1,
The composition for measuring the expression level of the protein is characterized in that the antibody or aptamer specific for the protein.
 제1항에 있어서,
상기 조성물은 갑상선 수술 여부와 수술 범위를 결정하기 위한 것을 특징으로 하는, 조성물.
The method of claim 1,
The composition is characterized in that for determining whether or not thyroid surgery and the surgical range, composition.
 피검체의 시료에서 하기 표 11 및 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 단계를 포함하는, 침윤성 EFVPTC와 NIFTP의 분류에 필요한 정보를 제공하는 방법.
[표 11]
Figure pat00081

[표 12]
Figure pat00082

A method of providing information necessary for classification of invasive EFVPTC and NIFTP, comprising measuring the mRNA expression level of one or more proteins selected from the group consisting of the proteins shown in Tables 11 and 12 below in a sample of a subject.
[Table 11]
Figure pat00081

[Table 12]
Figure pat00082

 제6항에 있어서,
상기 방법은 상기 표 11에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA의 발현이 검출되거나 또는 증가된 경우, NIFTP로 판정하는 단계를 더 포함하는 것을 특징으로 하는, 방법.
The method of claim 6,
The method further comprises the step of determining as NIFTP when the expression of one or more proteins selected from the group consisting of the proteins listed in Table 11 or mRNA thereof is detected or increased.
 제6항에 있어서,
상기 방법은 상기 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA의 발현이 검출되거나 또는 증가된 경우, 침윤성 EFVPTC로 판정하는 단계를 더 포함하는 것을 특징으로 하는, 방법.
The method of claim 6,
The method further comprises the step of determining as invasive EFVPTC when the expression of one or more proteins selected from the group consisting of the proteins listed in Table 12 or mRNA thereof is detected or increased.
 제6항에 있어서,
상기 시료는 혈액, 전혈, 혈장, 소변, 조직, 세포, 기관, 골수, 미세침 흡인 검체, 미세침 세척액, 중심부 생검 (core needle biopsy) 검체 및 타액으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 방법.
The method of claim 6,
The sample is characterized in that at least one selected from the group consisting of blood, whole blood, plasma, urine, tissue, cells, organs, bone marrow, fine needle aspiration specimen, fine needle washing liquid, core needle biopsy specimen, and saliva, Way.
 제6항에 있어서,
상기 단백질 발현 수준은 웨스턴 블랏, ELISA, 방사선면역분석, 방사선 면역 확산법, 오우크테로니 면역 확산법(Ouchterlony immunodiffusion), 로케트 면역전기영동(Rocket immunoelectrophoresis), 면역염색법, 면역침전 분석법, 보체 고정 분석법, 질량분석법(Mass spectrometry), FACS 및 단백질칩으로 이루어진 군으로부터 선택된 하나 이상의 방법으로 측정되는 것을 특징으로 하는, 방법.
The method of claim 6,
The protein expression level was Western blot, ELISA, radioimmunoassay, radioimmunoassay, Ouchterlony immunodiffusion, Rocket immunoelectrophoresis, immunostaining, immunoprecipitation assay, complement fixation assay, mass. Analytical method (Mass spectrometry), characterized in that the measurement by one or more methods selected from the group consisting of FACS and protein chip, method.
 제6항에 있어서,
상기 mRNA 발현 수준은 PCR, RNase 보호 분석법, 노던 블랏팅(northern blotting), 사우던 블랏팅(southern blotting), In situ 교잡법 및 DNA 칩으로 이루어진 군으로부터 선택된 하나 이상의 방법으로 측정되는 것을 특징으로 하는, 방법.
The method of claim 6,
The mRNA expression level is measured by one or more methods selected from the group consisting of PCR, RNase protection assay, northern blotting, southern blotting, in situ hybridization, and DNA chip. , Way.
 하기 표 11 및 표 12에 기재된 단백질로 이루어진 군으로부터 선택된 하나 이상의 단백질 또는 이의 mRNA 발현 수준을 측정하는 제제를 유효성분으로 포함하는 침윤성 EFVPTC와 NIFTP의 분류용 키트.
[표 11]
Figure pat00083

[표 12]
Figure pat00084

A kit for classification of invasive EFVPTC and NIFTP comprising, as an active ingredient, an agent for measuring the expression level of one or more proteins selected from the group consisting of the proteins described in Tables 11 and 12 below.
[Table 11]
Figure pat00083

[Table 12]
Figure pat00084
KR1020200137014A 2019-10-25 2020-10-21 Composition for Classification of Encapsulated Follicular variant of Papillary Thyroid Carcinoma(EFVPTC) with Non-invasive follicular thyroid neoplasm with papillary-like nuclear features(NIFTP) and Classification Method Using the Same KR102424264B1 (en)

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Citations (1)

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KR102011383B1 (en) * 2014-10-31 2019-08-16 에스케이텔레콤 주식회사 Composition for classifying the subtype of thyroid cancer

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Publication number Priority date Publication date Assignee Title
KR102011383B1 (en) * 2014-10-31 2019-08-16 에스케이텔레콤 주식회사 Composition for classifying the subtype of thyroid cancer

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Title
Baloch ZW, Seethala RR, Faquin WC, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): A changing paradigm in thyroid surgical pathology and implications for thyroid cytopathology. Cancer Cytopathol. 2016.
EBioMedicine, 2017, Vol. 18, pp 50-55. *
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