KR101049583B1 - A marker for diagnosing papillary thyroid cancer containing 3-indole acetonitrile as an active ingredient - Google Patents
A marker for diagnosing papillary thyroid cancer containing 3-indole acetonitrile as an active ingredient Download PDFInfo
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Abstract
본 발명은 3-인돌아세토니트릴을 유효성분으로 함유하는 유두갑상선암 진단용 마커에 관한 것이다. 본 발명에 따른 3-인돌아세토니트릴의 농도는 유두갑상선암 환자의 소변에서는 현저히 높고, 정상인의 소변에서는 현저히 낮게 나타나 비교적 간단한 방법으로 유두갑상선암의 진단 또는 예후를 조기에 예측할 수 있으므로, 유두갑상선암 진단용 마커로서 유용하게 사용될 수 있다.The present invention relates to a marker for diagnosing papillary thyroid cancer containing 3-indole acetonitrile as an active ingredient. Since the concentration of 3-indole acetonitrile according to the present invention is significantly high in the urine of papillary thyroid cancer patients, and is significantly low in the urine of normal persons, it is possible to predict the diagnosis or prognosis of papillary thyroid cancer early by a relatively simple method, and thus as a marker for diagnosing papillary thyroid cancer. It can be usefully used.
Description
본 발명은 3-인돌아세토니트릴을 유효성분으로 함유하는 유두갑상선암 진단용 마커에 관한 것이다.The present invention relates to a marker for diagnosing papillary thyroid cancer containing 3-indole acetonitrile as an active ingredient.
갑상선암은 갑상선체부에 발생하는 종양으로 임상에서 비교적 많이 보는 암이다. 보통 10만명에 2.3명꼴로 발생하며, 전체 악성종양 환자 중 1~3%를 차지한다. 갑상선암은 비교적 여성에게 많이 발생하고, 보통 7~20세 혹은 40~45세 사이에서 제일 많이 발생한다. 요오드 섭취 이상이나 갑상선 부분절제 등이 원인으로 꼽히며, 서양의학에서는 주로 수술요법, 방사선요법, 내분비요법, 화학요법 등으로 치료한다. 이러한 갑상선암에는 예후가 양호한 유두암 및 여포암과 예후가 좋지 않은 미분화암이 있으며, 그 외에 수질암, 임파선종이 있다. 이들 중 유두갑상선암 (PTC)은 갑상선암의 가장 일반적인 형태이며 그 증가속도가 가장 빠른 암중 하나로 알려져있다. 따라서, 유두갑상선암의 진단용 바이오마커 연구에 대한 관심이 높아져왔다.Thyroid cancer is a tumor that occurs in the thyroid gland and is a relatively common cancer. It occurs in 2.3 cases per 100,000 people, accounting for 1 to 3% of all malignant tumors. Thyroid cancer is more common in women and usually occurs most often between the ages of 7-20 and 40-45. The cause of abnormal iodine intake or partial thyroidectomy is the cause. In Western medicine, surgery, radiotherapy, endocrine therapy and chemotherapy are usually treated. These thyroid cancers include papillary and follicular cancers with a good prognosis and undifferentiated cancers with a poor prognosis, as well as medulla and lymphadenoma. Of these, papillary thyroid cancer (PTC) is the most common form of thyroid cancer and is known to be one of the fastest growing cancers. Therefore, there has been a growing interest in the study of diagnostic biomarkers for papillary thyroid cancer.
유두갑상선암 환자를 진단하는 마커에 대한 기존 연구는 크게 유전자 서열, microRNA, 단백질 분자를 중점으로 수행되었다. 그 예로, Ras, BRAF 신호전달 경로에 해당하는 유전자들에 돌연변이가 생겼을 경우 유두갑상선암 환자의 예후가 좋지 않다는 연구 보고가 있었으며 (A.M. Costa, A. Herrero, M.F. Fresno, J. Heymann, J.A. Alvarez, J. Cameselle-Teijeiro, and G. Garcia-Rostan, BRAF mutation associated with other genetic events identifies a subset of aggressive papillary thyroid carcinoma. Clin Endocrinol (Oxf) 68 (2008) 618-34.), 유두갑상선암 환자에서 miR-221과 R-222 microRNA의 과잉발현이 보고되었다 (G.A. Calin, and C.M. Croce, MicroRNA signatures in human cancers. Nat Rev Cancer 6 (2006) 857-66.). 또한 유두갑상선 암환자에서 차이를 보이는 단백질로 MDM4의 전사 저발현이 보고되었으며 (A. Prodosmo, S. Giglio, S. Moretti, F. Mancini, F. Barbi, N. Avenia, G. Di Conza, H.J. Schunemann, L. Pistola, V. Ludovini, A. Sacchi, A. Pontecorvi, E. Puxeddu, and F. Moretti, Analysis of human MDM4 variants in papillary thyroid carcinomas reveals new potential markers of cancer properties. J Mol Med 86 (2008) 585-96.) cytokeratin-19 와 galectin-3 의 과잉 발현이 보고되었다 (K.M. Murphy, F. Chen, and D.P. Clark, Identification of immunohistochemical biomarkers for papillary thyroid carcinoma using gene expression profiling. Hum Pathol 39 (2008) 420-6.).Existing studies of markers for diagnosing papillary thyroid cancer patients have largely focused on gene sequences, microRNAs, and protein molecules. For example, there have been reports of poor prognosis in papillary thyroid cancer patients with mutations in genes corresponding to Ras and BRAF signaling pathways (AM Costa, A. Herrero, MF Fresno, J. Heymann, JA Alvarez, J). Cameselle-Teijeiro, and G. Garcia-Rostan, BRAF mutation associated with other genetic events identifies a subset of aggressive papillary thyroid carcinoma.Clin Endocrinol (Oxf) 68 (2008) 618-34.), MiR-221 in patients with papillary thyroid cancer And overexpression of R-222 microRNA (GA Calin, and CM Croce, MicroRNA signatures in human cancers. Nat Rev Cancer 6 (2006) 857-66.). In addition, a low protein expression of MDM4 has been reported in papillary thyroid cancer patients (A. Prodosmo, S. Giglio, S. Moretti, F. Mancini, F. Barbi, N. Avenia, G. Di Conza, HJ). Schunemann, L. Pistola, V. Ludovini, A. Sacchi, A. Pontecorvi, E. Puxeddu, and F. Moretti, Analysis of human MDM4 variants in papillary thyroid carcinomas reveals new potential markers of cancer properties.J Mol Med 86 (2008 Overexpression of cytokeratin-19 and galectin-3 has been reported (KM Murphy, F. Chen, and DP Clark, Identification of immunohistochemical biomarkers for papillary thyroid carcinoma using gene expression profiling. Hum Pathol 39 (2008)) 420-6.).
통상 이러한 진단마커들은 개체로부터 시료를 얻기 위해 조직을 얻어내야하는 침습적 실험을 필요로 하며, 대부분의 진단마커로 단백질 분자를 사용한다. 즉, 신체유체(bio-fluid) 중 정상인 대비 암환자에서 유의한 변화를 보이는 분자물질을 찾는 방식으로 진행되고 있다. 하지만 이러한 방식으로 찾아진 진단 마커는 재현성이 낮다는 문제점을 갖고 있으며, 또한 암세포로부터 기원된 물질이라는 해석이 힘들다는 문제점들이 있었다.Typically, these diagnostic markers require invasive experiments that require obtaining tissue from a subject to obtain a sample, and most diagnostic markers use protein molecules. In other words, the bio-fluid is being searched for molecular substances that show significant changes in cancer patients compared to normal people. However, the diagnostic marker found in this way has a problem of low reproducibility, and also has a problem in that it is difficult to interpret a substance derived from cancer cells.
따라서, 상기와 같은 문제점들을 극복하고 암세포에서 기원하는 대사물질을 이용하여 간편하게 유두갑상선암을 진단할 수 있는 마커에 대한 개발의 필요성이 요구되고 있다.Therefore, there is a need to overcome the above problems and to develop a marker that can easily diagnose papillary thyroid cancer using metabolites originating from cancer cells.
본 발명자들은 암세포에서 기원하는 대사물질을 이용하여 간편하게 유두갑상선암을 진단할 수 있는 마커에 대해 연구하던 중, 암세포 자체의 특이적 대사 작용과 관련된 대사물질을 유전자 발현 정보와 대사 경로 정보를 이용하여 찾았으며, 이러한 대사물질의 농도가 유두갑상선암 환자의 소변에서는 현저히 높고, 정상인의 소변에서는 현저히 낮은 것을 확인하고, 본 발명을 완성하였다.The inventors of the present invention have been searching for markers for diagnosing papillary thyroid cancer using metabolites originating from cancer cells, and searching for metabolites related to specific metabolism of cancer cells using gene expression information and metabolic pathway information. The concentration of these metabolites was significantly higher in the urine of papillary thyroid cancer patients, and significantly lower in the urine of normal persons, thus completing the present invention.
본 발명은 3-인돌아세토니트릴을 유효성분으로 함유하는 유두갑상선암 진단용 마커를 제공하고자 한다.The present invention is to provide a marker for diagnosing papillary thyroid cancer containing 3-indole acetonitrile as an active ingredient.
본 발명은 3-인돌아세토니트릴을 유효성분으로 함유하는 유두갑상선암 진단용 마커를 제공한다.The present invention provides a marker for diagnosing papillary thyroid cancer containing 3-indole acetonitrile as an active ingredient.
또한, 본 발명은 생체 시료에서 유두갑상선암 진단용 마커인 3-인돌아세토니트릴의 농도 차이를 검출하는 방법을 제공한다.The present invention also provides a method for detecting a difference in concentration of 3-indole acetonitrile, which is a diagnostic marker for papillary thyroid cancer, in a biological sample.
이하, 본 발명에 대해 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 암세포 자체의 특이적 대사 작용과 관련된 대사물질을 유전자 발현 정보와 대사 경로 정보를 이용하여 암세포에서 변화를 보이는 대사 경로의 대사물질들 중에서 그 농도가 정상인 대비 유두갑상선암 환자의 생체 시료에서 유의한 변화를 보이는 대사물질을 검출하여 유두갑상선암에 대한 마커로서 제공한다. 구체 적으로는, 유두갑상선암 세포에서 유의한 변화를 보이는 14 종류의 대사 경로에 해당하는 대사물질들 중 공개된 질량 스펙트럼 라이브러리(mass spectrum library)를 갖는 122개의 후보 대사물질을 암환자와 정상군의 생체 시료에서 t-test로 측정하여 상기 후보 대사물질들 중 16개의 대사물질들이 환자군과 정상군에서 농도 차이가 나타남을 확인하였다. 이들 중 3-인돌아세토니트릴이 환자군과 정상군 사이에서 가장 유의한 차이를 나타내었다(p-value < 5.16E-12)(표 3 참조). 따라서, 본 발명에 따른 유두갑상선암 세포 자체의 특이적 대사 작용과 관련된 대사물질을 3-인돌아세토니트릴로 동정하였다.According to the present invention, metabolites related to specific metabolic activity of cancer cells themselves are significant in biological samples of papillary thyroid cancer patients compared to normal concentrations of metabolites of metabolic pathways showing changes in cancer cells using gene expression information and metabolic pathway information. Metabolites showing one change are detected and served as markers for papillary thyroid cancer. Specifically, among the 14 metabolic pathways with significant changes in papillary thyroid cancer cells, 122 candidate metabolites with published mass spectrum libraries were identified. By measuring t-test in the biological sample, it was confirmed that 16 metabolites among the candidate metabolites showed a difference in concentration between the patient group and the normal group. Among these, 3-indoleacetonitrile showed the most significant difference between the patient group and the normal group (p-value <5.16E-12) (see Table 3). Therefore, metabolites related to specific metabolic activity of papillary thyroid cancer cells themselves according to the present invention were identified as 3-indoleacetonitrile.
상기 생체 시료는 혈액, 혈청, 복막 세정물, 뇌하수액, 타액, 소변 및 대변을 포함하나 이에 한정되지 않으며, 본 발명에서는 소변이 가장 바람직하다.The biological sample includes, but is not limited to, blood, serum, peritoneal lavage, pituitary fluid, saliva, urine and feces, urine is most preferred in the present invention.
상기 3-인돌아세토니트릴의 농도 차이는 액체 크로마토그래피/질량 분석기, 기체 크로마토그래피/질량 분석기, 또는 텐덤 질량분석기를 이용하여 검출할 수 있다.The concentration difference of the 3-indoleacetonitrile can be detected using a liquid chromatography / mass spectrometer, a gas chromatography / mass spectrometer, or a tandem mass spectrometer.
상기 3-인돌아세토니트릴의 농도 차이는 암 대 비-암(non-cancer), 악성 종양 대 양성 종양, 침습성 암 대 잠복성 암의 생체 시료에서 검출할 수 있다.The concentration difference of the 3-indoleacetonitrile can be detected in a biological sample of cancer vs. non-cancer, malignant vs. benign tumor, and invasive vs. latent cancer.
본 발명에 따른 3-인돌아세토니트릴의 농도는 유두갑상선암 환자의 소변에서는 현저히 높고, 정상인의 소변에서는 현저히 낮게 나타난다. 또한, 3-인돌아세토니트릴은 정확도, 민감도, 특이도 모두 99% 이상의 매우 좋은 분류 성능을 나타낸다. 따라서, 본 발명에 따른 3-인돌아세토니트릴은 비교적 간단한 방법으로 유두갑상선암의 진단 또는 예후를 조기에 예측할 수 있으므로, 유두갑상선암 진단용 마커 로서 유용하게 사용될 수 있다.The concentration of 3-indoleacetonitrile according to the present invention is markedly high in the urine of papillary thyroid cancer patients, and significantly lower in the urine of normal persons. In addition, 3-indoleacetonitrile exhibits very good classification performance of more than 99% in accuracy, sensitivity and specificity. Therefore, since 3-indole acetonitrile according to the present invention can predict the diagnosis or prognosis of papillary thyroid cancer early by a relatively simple method, it can be usefully used as a marker for diagnosing papillary thyroid cancer.
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, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.
실시예 1Example 1 : 3-인돌아세토니트릴의 대사물질 마커의 동정 : Identification of Metabolite Markers of 3-indoleacetonitrile
1. 유전자 발현 정보1. Gene Expression Information
본 발명에서 사용한 유전자 발현 정보는 2005년 발표된 논문에서 제공하고 있는 데이터를 사용하였다(Jarzab, B., Wiench, M., Fujarewicz, K., Simek, K., Jarzab, M., Oczko-Wojciechowska, M., Wloch, J., Czarniecka, A., Chmielik, E., Lange, D., et al. (2005) Cancer research 65, 1587-1597). 해당 데이터는 총 23개의 유두갑상선암 환자와 17개의 정상군에서 추출된 유전자 별현 정보를 포함하고 있다.Gene expression information used in the present invention used data provided in the paper published in 2005 (Jarzab, B., Wiench, M., Fujarewicz, K., Simek, K., Jarzab, M., Oczko-Wojciechowska , M., Wloch, J., Czarniecka, A., Chmielik, E., Lange, D., et al. (2005) Cancer research 65, 1587-1597). The data included gene expression information from 23 papillary thyroid cancer patients and 17 normal groups.
2. 환자 샘플 수집2. Patient Sample Collection
삼성 병원, 한양대학 병원에서 수집된 14명의 유두갑상선암 환자(나이 53.29±15.77년)와 14명의 정상군(나이 51.86±11.72년)에서 수집된 소변 샘플을 사용하였다. 사용된 소변 샘플은 모두 이른 오전에 수집되었다.Urine samples were collected from 14 patients with papillary thyroid cancer (53.29 ± 15.77 years) and 14 normal patients (51.86 ± 11.72 years) collected from Samsung Hospital and Hanyang University Hospital. All urine samples used were collected early in the morning.
3. 통계적 분석3. Statistical Analysis
본 발명에서 사용하고 있는 대사 정보데이터는 (1) 대사 경로 정보, (2) 전사 조절 정보, (3) 유전자 발현 정보가 있다. 유두갑상선암 세포에서 유의한 변화를 보이는 대사 경로들(FDR≤0.05)은 표 1에 나타내었으며, 암진단 마커의 발굴 과 정은 도 1에 나타내었다.Metabolic information data used in the present invention includes (1) metabolic pathway information, (2) transcriptional regulation information, and (3) gene expression information. Metabolic pathways (FDR≤0.05) showing significant changes in papillary thyroid cancer cells are shown in Table 1, and the discovery process of cancer diagnosis markers is shown in FIG.
마이크로어레이를 이용한 유전자 발현 정보는 t-test를 거쳐서 각각의 유전자의 발현의 변화 유의성을 나타내는 z-score로 나타내어진다. 그 후 유전자 발현의 변화 유의성 점수는 각각의 대사 경로의 효소와 그의 전사 조절체에 매핑되어 해당 대사 경로가 조건 하에서 증진되는지 감소되는지를 판단하게 된다(도 1).Gene expression information using a microarray is represented by z-score indicating the significance of change in the expression of each gene through t-test. The change significance score of gene expression is then mapped to enzymes and transcriptional regulators of each metabolic pathway to determine whether the metabolic pathway is enhanced or decreased under conditions (FIG. 1).
본 발명에서 사용하는 점수함수(scoring function)는 대사 작용의 특징을 살려서 속도결정단계(rate-determining step)와 같이 주요한 변화를 보이는 효소 작용을 감지하게 된다. 제안하는 방법은 암세표의 유전자 발현 데이터에 적용되며, 정상인 대비 암환자에서 변화하는 대사 경로를 찾을 수 있었다(표 1).Scoring function used in the present invention is to take advantage of the characteristics of the metabolic activity to detect the enzyme action showing a major change, such as the rate-determining step. The proposed method is applied to the gene expression data of the cancer table, and found that metabolic pathways change in cancer patients compared to normal people (Table 1).
4. 대사물질 마커 후보군4. Metabolite Marker Candidates
유두갑상선암 세포에서 유의한 변화를 보이는 14 종류의 대사 경로에 해당하는 대사물질들 중 공개된 질량 스펙트럼 라이브러리를 갖는 대사물질은 122개가 있으며, 하기 표 2에 나타내었다. 이들은 유두갑상선암 세포에서 유의한 변화를 보이는 대사 경로들을 기반으로 한 마커 후보군들이다. 이러한 122개의 후보 대사물질을 암환자와 정상군의 소변 샘플에서 t-test로 측정하였으며, 측정 결과는 표 3에 나타내었다.Among metabolites corresponding to 14 kinds of metabolic pathways showing significant changes in papillary thyroid cancer cells, there are 122 metabolites having a published mass spectrum library, and are shown in Table 2 below. These are marker candidates based on metabolic pathways that show significant changes in papillary thyroid cancer cells. These 122 candidate metabolites were measured by t-test in urine samples of cancer patients and normal groups, and the measurement results are shown in Table 3.
표 3에 나타난 바와 같이, t-test 양측검정 결과 122개의 후보 대사물질 중 16개의 대사물질들이 환자군과 정상군에서 농도 차이를 나타내었으며, 이들 중 3-인돌아세토니트릴이 환자군과 정상군 사이에서 가장 유의한 차이를 나타내었다(p-value < 5.16E-12). 따라서, 본 발명에 따른 유두갑상선암 세포 자체의 특이적 대사 작용과 관련된 대사물질을 3-인돌아세토니트릴로 동정하였다.As shown in Table 3, t-test bilateral testing revealed 16 metabolites out of 122 candidate metabolites in the patient and normal groups, of which 3-indoleacetonitrile was the most common between the patient and normal groups. A significant difference was shown (p-value <5.16E-12). Therefore, metabolites related to specific metabolic activity of papillary thyroid cancer cells themselves according to the present invention were identified as 3-indoleacetonitrile.
실험예 1Experimental Example 1 : 3-인돌아세토니트릴의 마커 성능 : Marker Performance of 3-Indolacetonitrile
1. 3-인돌아세토니트릴의 농도 차이1. Concentration Differences in 3-Indolacetonitrile
이러한 암세포에서 변화를 보이는 대사 경로의 대사물질들 중에서 그 농도가 정상인 대비 유두갑상선암 환자의 소변에서 유의한 변화를 보이는 대사산물을 GC/MS로 탐색하였다.Among metabolites of metabolic pathways showing changes in these cancer cells, metabolites showing significant changes in urine of papillary thyroid cancer patients compared to normal concentrations were searched by GC / MS.
결과는 도 2에 나타내었다.The results are shown in Fig.
도 2에 나타난 바와 같이, 3-인돌아세토니트릴의 농도가 유두갑상선암 환자의 소변에서는 현저히 높고, 정상인의 소변에서는 현저히 낮은 것을 확인하였다. 즉, 대사물질들 중에서 3-인돌아세토니트릴의 농도 차이가 유의하게 다르다는 것을 알 수 있다.As shown in Figure 2, it was confirmed that the concentration of 3-indole acetonitrile was significantly high in the urine of papillary thyroid cancer patients, and significantly low in the urine of normal people. That is, it can be seen that the concentration difference of 3-indoleacetonitrile among metabolites is significantly different.
2. 3-인돌아세토니트릴의 정확도, 민감도, 특이도 측정2. Measurement of accuracy, sensitivity and specificity of 3-indoleacetonitrile
3-인돌아세토니트릴의 농도를 소변 샘플에서 관찰할 경우 어느 정도로 암환자와 정상인을 판별할 수 있는지 알아보기 위하여 기계학습기반의 분류 실험을 수행하였다. 본 발명에서는 선형판별분석(Linear Discriminative Analysis, LDA), RF (Random Forest), SVM(Support Vector Machine)의 세 가지 분류 실험으로 3-인돌아세토니트릴 마커의 성능을 실험하여 정확도, 민감도, 특이도를 측정하였다.Machine learning-based classification experiments were performed to determine the extent to which cancer patients and normal subjects could be determined when the concentration of 3-indoleacetonitrile was observed in urine samples. In the present invention, three classification experiments, Linear Discriminative Analysis (LDA), Random Forest (RF), and Support Vector Machine (SVM), are conducted to test the performance of the 3-indolacetonitrile markers to determine accuracy, sensitivity, and specificity. Measured.
결과는 도 3에 나타내었다.The results are shown in FIG.
도 3에 나타난 바와 같이, 3-인돌아세토니트릴은 정확도, 민감도, 특이도 모두 99% 이상의 매우 좋은 분류 성능을 나타내었다.As shown in Figure 3, 3-indole acetonitrile showed very good classification performance of more than 99% in accuracy, sensitivity, specificity.
본 발명에 따른 3-인돌아세토니트릴의 농도는 유두갑상선암 환자의 소변에서는 현저히 높고, 정상인의 소변에서는 현저히 낮게 나타나 비교적 간단한 방법으로 유두갑상선암의 진단 또는 예후를 조기에 예측할 수 있으므로, 유두갑상선암 진단용 마커로서 유용하게 사용될 수 있다.Since the concentration of 3-indole acetonitrile according to the present invention is significantly high in the urine of papillary thyroid cancer patients, and is significantly low in the urine of normal persons, it is possible to predict the diagnosis or prognosis of papillary thyroid cancer early by a relatively simple method, and thus as a marker for diagnosing papillary thyroid cancer. It can be usefully used.
도 1은 암진단 마커의 발굴 과정을 나타낸 도이다.1 is a diagram illustrating a process of discovering a cancer diagnostic marker.
도 2는 3-인돌아세토니트릴이 정상인 대비 유두갑상선암 환자의 소변에서 유의한 농도 차이를 나타낸 도이다.Figure 2 is a diagram showing the difference in concentration in the urine of patients with papillary thyroid cancer compared to normal 3-indolacetonitrile.
도 3은 3-인돌아세토니트릴의 정확도, 민감도, 특이도를 나타낸 도이다.Figure 3 is a diagram showing the accuracy, sensitivity, specificity of 3-indole acetonitrile.
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