WO2012115308A1 - Method and apparatus for diagnosing thyroid cancer - Google Patents
Method and apparatus for diagnosing thyroid cancer Download PDFInfo
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- WO2012115308A1 WO2012115308A1 PCT/KR2011/003133 KR2011003133W WO2012115308A1 WO 2012115308 A1 WO2012115308 A1 WO 2012115308A1 KR 2011003133 W KR2011003133 W KR 2011003133W WO 2012115308 A1 WO2012115308 A1 WO 2012115308A1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
- G01N33/743—Steroid hormones
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
- G01N33/78—Thyroid gland hormones, e.g. T3, T4, TBH, TBG or their receptors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
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- G—PHYSICS
- G06—COMPUTING OR CALCULATING; COUNTING
- G06F—ELECTRIC DIGITAL DATA PROCESSING
- G06F17/00—Digital computing or data processing equipment or methods, specially adapted for specific functions
- G06F17/10—Complex mathematical operations
- G06F17/18—Complex mathematical operations for evaluating statistical data, e.g. average values, frequency distributions, probability functions, regression analysis
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
- G16H50/70—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for mining of medical data, e.g. analysing previous cases of other patients
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- the present invention relates to a method and a diagnostic apparatus for thyroid cancer, and more particularly, to a thyroid cancer diagnosis method and diagnostic apparatus that can significantly diagnose thyroid cancer based on the statistics of hormone concentrations obtained from a body sample.
- Thyroid cancer is more common among men than women, and the cancer incidence rate of the National Cancer Information Center is 7.4% of all cancers in 2002. According to the recent report to the Korean Society of Thyroid Diseases, Korea ranked fourth in cancer incidence in 2006 and women in first place. Thyroid cancer has a higher incidence than other cancers, but if the diagnosis is made early and surgery can be done early, survival is higher.
- thyroid cancer The causes of thyroid cancer are known as radiation exposure, sex hormones, etc., but the exact cause is still unknown (Tronko ND, et al. Thyroid gland and radiation (Ukrainian-American Thyroid Project). International Congress Series 2003; 1258: Robbins J, Schneider AB.Radioiodine-induced thyroid cancer: Studies in the aftermath of the accident at Chernobyl. Trends Endocrinol Metab 1998; 9: 87-94.). It is very important to identify risk factors for thyroid cancer and use them to establish a prevention system for thyroid cancer. Moreover, since thyroid cancer is detected early and has a very high survival rate, it is also important to establish a method for early and accurate diagnosis. Currently screening for thyroid disease uses ultrasound, and no special preventive method is known.
- 2-methoxyestradiol (2-MeO-E2) exhibits anti-proliferative and apoptotic effects in thyroid cancer cells (Roswall P, et al. 2-methoxyestradiol induces apoptosis in cultured) human anaplastic thyroid carcinoma cells.Thyroid. 2006 Feb; 16 (2): 143-50).
- 16 ⁇ -OHE1 is recognized as a risk factor because it is involved in cancer proliferation.
- the present inventors have reliably studied the thyroid cancer disease and its progression method, and as a result, we established a hormone group that significantly increases the mean value in the body samples of thyroid cancer patients compared to normal people, The present invention has been completed by developing a method for reliably diagnosing thyroid cancer using the hormone group.
- an object of the present invention is to provide a thyroid cancer diagnosis method for reliably diagnosing thyroid cancer using concentrations of hormone groups measured in body samples.
- Another object of the present invention is to provide a thyroid cancer diagnosis apparatus capable of reliably diagnosing thyroid cancer using concentrations of hormone groups measured in body samples.
- a thyroid cancer diagnosis method for determining whether or not thyroid cancer progresses by comparing statistical values obtained by using hormone concentrations as data.
- 2-hydroxyestron (2-OH-E1), 2-hydroxyestradiol (2-OH-E2) measured from body samples from populations of normal and thyroid cancer patient groups, respectively, to provide the information needed to diagnose thyroid cancer , 2-methoxy estrone (2-MeO-E1), 2-methoxy estradiol (2-MeO-E2), and 2-methoxy estradiol-3-methyl ether (2-MeO-E2-3-methyl
- Hormone concentration input unit for inputting the hormone concentration measured from the body sample of the diagnosis object
- Statistical values obtained by using hormone concentrations as data are stored, and the sample values of the diagnosis subjects are calculated based on the statistical values using the three or more hormone concentrations input through the input unit, and the sample values of the diagnosis subjects.
- a thyroid cancer diagnosis device which is a computer system including an output unit for outputting the diagnosis result.
- the present inventors studied a method for reliably diagnosing thyroid cancer disease, and as a result, for the first time, we established a hormone group in which the mean value of the thyroid cancer patient group was significantly increased compared to the normal group.
- the five hormone groups have very high variability in changes in the concentration of thyroid cancer patients with respect to the normal group, there may be an increase in false positive results when only comparing the absolute value of the hormone concentration.
- the statistics obtained by using three or more hormone concentrations among the five hormone groups as data are compared with the corresponding values of the three or more hormone concentrations (ie, sample values for diagnosis) of the body sample to be diagnosed, or The method of determining the progress was devised.
- a thyroid cancer diagnosis method for determining whether or not thyroid cancer progresses by comparing statistical values obtained by using hormone concentrations as data.
- 2-hydroxyestron (2-OH-E1), 2-hydroxyestradiol (2-OH-E2) measured from body samples from populations of normal and thyroid cancer patient groups, respectively, to provide the information needed to diagnose thyroid cancer , 2-methoxy estrone (2-MeO-E1), 2-methoxy estradiol (2-MeO-E2), and 2-methoxy estradiol-3-methyl ether (2-MeO-E2-3-methyl
- the "statistics obtained by using three or more hormone concentrations as data” means statistical values obtained by any statistical method from three or more hormone concentrations measured from body samples of the populations of the normal group and the thyroid cancer patient group, respectively. It is a statistical value that can determine the progress or progression of thyroid cancer compared to the sample value of the diagnosis target.
- the "sample value of the diagnosis subject” refers to a value corresponding to the statistical value of the three or more hormone concentrations measured from a body sample of the subject to be diagnosed.
- the "statistic obtained by using three or more hormone concentrations as data” is not particularly limited, but is preferably a regression equation obtained using multiple regression analysis. Specifically, in all possible cases where data of three or more hormone concentrations measured from the body samples of the respective populations of the normal group and the thyroid cancer patient group are used, and the order of disease progression is arbitrarily determined for some or all of the normal group and the thyroid cancer patient group.
- a regression equation obtained by multiple regression analysis on numbers can be used as a thyroid disease index, and the regression equation can be used as a statistical value obtained by using the three or more hormone concentrations as data.
- the regression equation has a coefficient of determination (r 2 ) of 0.6 or more as a result of multiple regression analysis, it is preferred that the highest regression equation.
- the thyroid disease index (ie, the sample value of the diagnosis target) obtained by substituting the three or more hormone concentrations of the body sample to be diagnosed into the expression of the thyroid disease index, it is possible to diagnose whether or not the progression of thyroid cancer. More specifically, when determining the regression equation by the multiple regression analysis, the thyroid disease index value in the case of thyroid cancer, the thyroid disease index value in the case of normal, the transition stage from normal to thyroid cancer based on the population data
- the thyroid disease index value ie, a sample value for diagnosis obtained by setting the thyroid disease index value as a reference value and substituting the three or more hormone concentrations of the body sample to be diagnosed into the regression formula belongs to any region of the reference value. It can determine whether thyroid cancer is present and how far it progresses.
- the normal group and the thyroid cancer patient group cannot use the binary data to obtain the regression equation, and all or part of the thyroid cancer disease group and the normal group are arranged at random in all possible cases of disease progression for each individual, and in all cases.
- the regression equation can be obtained by performing multiple regression analysis on.
- the body sample can be any body sample capable of measuring the three or more hormone concentrations, for example urine, blood, or saliva can be used.
- urine or serum in blood may be used.
- the hormone concentration measurement method may be performed by any method known in the art, for example, GC-MS-SIM (Gas Chromatography- Mass Spectrometry-Selected Ion-Monitorng), HPLC (High-performance liquid) chromatography, and EIA (competitive solid-phase enzyme immunoassay).
- GC-MS-SIM Gas Chromatography- Mass Spectrometry-Selected Ion-Monitorng
- HPLC High-performance liquid
- EIA competitive solid-phase enzyme immunoassay
- the three or more hormone concentrations are more preferably four or more hormone concentrations.
- the use of four or more hormone concentrations as data for obtaining the statistics or the thyroid disease index can further increase the reliability of thyroid cancer diagnosis.
- the four or more hormones may include, for example, 2-hydroxyestrone, 2-hydroxyestradiol, 2-methoxyestradiol, and 2-methoxyestradiol-3-methylether.
- a regression equation obtained by multiple regression analysis using at least four hormone concentrations measured from body samples of a population of each of the normal and thyroid cancer patient groups is as follows:
- Thyroid Disease Index 0.0153x2-MeO-E2-3-methylether + 0.0874x2-MeO-E2 / 2-OH-E2-2.2571x2-MeO-E2-3-methylether / 2-OH-E1 + 0.5649
- the disease index is between 0 and 0.8, and the thyroid cancer patient group is 1.0 or more.
- 0.8 to 1.0 is a borderline thyroid cancer risk group.
- the thyroid cancer diagnosis method may be implemented as a thyroid cancer diagnosis apparatus, and may provide a thyroid cancer diagnosis apparatus capable of knowing whether or not the thyroid cancer progresses by inputting a hormone concentration measured in a body sample to be diagnosed.
- Hormone concentration input unit for inputting the hormone concentration measured from the body sample of the diagnosis object
- Statistical values obtained by using hormone concentrations as data are stored, and the sample values of the diagnosis subjects are calculated based on the statistical values using the three or more hormone concentrations input through the input unit, and the sample values of the diagnosis subjects.
- a thyroid cancer diagnosis device which is a computer system including an output unit for outputting the diagnosis result.
- the diagnostic program module stores a regression equation obtained by multiple regression analysis as a formula of thyroid disease index using at least three hormone concentrations measured from body samples of the populations of the normal group and the thyroid cancer patient group as data. It may include a program for determining whether or not the progression of thyroid cancer according to the thyroid disease index obtained by substituting the three or more hormone concentrations of the body sample of the diagnosis subject input through the formula into the formula of the stored thyroid disease index.
- the program may be designed in such a manner as to perform a thyroid cancer diagnostic method according to an aspect of the present invention described above, and may be designed in such a manner as to perform all possible embodiments of the thyroid cancer diagnostic method according to an aspect of the present invention. Can be. It is apparent that the program that the diagnostic program module should have to perform this design can be designed by those skilled in the computer program field using the knowledge known in the present specification and the computer program field.
- the thyroid cancer diagnosis device may automatically activate the diagnostic program module by outputting three or more hormone concentrations measured from a body sample of a diagnosis target to a hormone concentration input unit so that a thyroid cancer diagnosis result may be automatically output through an output unit.
- the operation of the diagnostic program module and the output of the diagnosis result may be performed by a separate manual operation.
- the input of the three or more hormone concentrations measured from the body sample to be diagnosed may be inputted separately after measuring by a measuring device, but the hormone concentration for the thyroid cancer diagnostic device to measure the hormone concentration from the body sample.
- You may further comprise a measuring instrument. That is, the diagnostic apparatus further includes a hormone concentration measuring device for measuring hormone concentration from a body sample of the diagnosis target, and the hormone concentration measuring device is connected to the hormone concentration input unit so that the hormone concentration measured by the hormone concentration measuring device is automatically input. You can do that.
- the hormone concentration meter may be any meter capable of measuring the five hormone concentrations, for example, a GC-MS-SIM device (Gas Chromatography-Mass Spectrometry-Selected Ion-Monitorng), HPLC (High-performance liquid) chromatography, an EIA (competitive solid-phase enzyme immunoassay).
- a GC-MS-SIM device Gas Chromatography-Mass Spectrometry-Selected Ion-Monitorng
- HPLC High-performance liquid
- EIA competitive solid-phase enzyme immunoassay
- the thyroid cancer diagnosis method and apparatus can diagnose the thyroid cancer and the progress of the thyroid cancer by measuring the hormone concentration of three or more of the five hormones in the body sample to be diagnosed.
- the thyroid cancer can be diagnosed by measuring hematological changes, the thyroid cancer can be diagnosed earlier.
- the method and diagnostic apparatus for thyroid cancer according to the present invention is very innovative due to the characteristics of thyroid cancer in which early diagnosis is important.
- the disease index is a graph showing the hormone concentration data and the thyroid disease index according to the disease progression sequence in which the regression equation is obtained.
- GC-MS-SIM gas chromatograph-mass spectrometry-selected ion-monitoring
- thyroid cancer patients Information on thyroid cancer patients is summarized in Table 1 below. Of the thyroid cancer patients, 18 were female, 5 were male, and their age ranged from 26 to 60 years. There are 11 thyroid cancers, 6 thyroid tumors, 3 thyroid masses, 1 thyroid papillary cancer, and 1 goiter. In the following table, pre / post means pre / post surgery.
- T-test analysis was performed on the measured hormone profile data to find risk factors for thyroid disease.
- the t-test results are summarized in Table 2 below.
- MLR Multiple linear regression
- Thyroid Disease Index 0.0153 x 2-MeO-E2-3-methylether + 0.0874 x 2-MeO-E2 / 2-OH-E2-2.2571 x 2-MeO-E2-3-methylether / 2-OH -E1 + 0.5649
- FIG. 1 the thyroid disease index and the hormone concentration data according to the disease progression sequence obtained are shown in a graph.
- the thyroid disease index of 0 to 0.8 was found to be a normal group, and the index 1.0 or more was shown to be a thyroid cancer patient group.
- the first four patients at the borderline below the index 1.0 were thyroid mass (0.8055), goiter (0.8806), thyroid mass (preoperative thyroid cancer, 0.8951), and thyroid mass (preoperative thyroid cancer). , 0.9112).
- the optimal regression equation of the acquired thyroid disease index increases in accordance with the progression of thyroid cancer, so that the thyroid disease can be classified according to the regression equation. Therefore, it is possible to determine whether thyroid cancer and the progression of thyroid cancer based on the range of the thyroid disease index obtained according to the obtained thyroid disease index, it is understood that the thyroid disease index (TDI) is a good tool for diagnosis of thyroid cancer Can be.
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Abstract
Description
본 발명은 갑상선암 진단방법 및 진단장치에 관한 것으로, 보다 구체적으로는 신체 샘플로부터 얻을 수 있는 호르몬 농도의 통계치에 기초하여 갑상선암을 유의적으로 진단할 수 있는 갑상선암 진단방법 및 진단장치에 관한 것이다.The present invention relates to a method and a diagnostic apparatus for thyroid cancer, and more particularly, to a thyroid cancer diagnosis method and diagnostic apparatus that can significantly diagnose thyroid cancer based on the statistics of hormone concentrations obtained from a body sample.
갑상선암은 남성보다는 특히 여성에게 많이 발병되는 암으로써 국가암정보센터의 암 발병률을 살펴보면 2002년 기준 여성 전체 암의 7.4%를 차지하고 있다. 최근 대한갑상선 질병학회에 보고된 자료에 의하면 2006년 기준 국내 암 발병률의 4위를 차지하고 있으며 여성의 경우는 1위를 차지하고 있다. 갑상선암은 다른 암에 비해 발병률이 높기는 하지만 진단이 조기에 이루어져 조기에 수술을 할 수 있다면 생존률이 높은 편에 속한다. Thyroid cancer is more common among men than women, and the cancer incidence rate of the National Cancer Information Center is 7.4% of all cancers in 2002. According to the recent report to the Korean Society of Thyroid Diseases, Korea ranked fourth in cancer incidence in 2006 and women in first place. Thyroid cancer has a higher incidence than other cancers, but if the diagnosis is made early and surgery can be done early, survival is higher.
갑상선암의 원인은 방사선 노출, 성호르몬 등으로 알려져 있으나 아직 정확한 원인에 대한 규명은 이루어지지 않고 있다(Tronko ND, et al. Thyroid gland and radiation (Ukrainian-American Thyroid Project). International Congress Series 2003;1258:91-104; Robbins J, Schneider AB. Radioiodine-induced thyroid cancer: Studies in the aftermath of the accident at Chernobyl. Trends Endocrinol Metab 1998;9:87-94.). 갑상선암에 대한 위험인자를 찾아내고 이를 활용하여 갑상선암에 대한 예방 시스템을 구축 하는 것은 매우 중요하다. 더욱이, 갑상선암은 조기에 발견하여 수술하면 생존율이 매우 높으므로 조기에 정확하게 진단하는 방법을 구축하는 것 또한 매우 중요하다. 현재 갑상선 질병의 검진은 초음파를 이용하고 있으며, 특별한 예방법이 알려져 있지 않다. The causes of thyroid cancer are known as radiation exposure, sex hormones, etc., but the exact cause is still unknown (Tronko ND, et al. Thyroid gland and radiation (Ukrainian-American Thyroid Project). International Congress Series 2003; 1258: Robbins J, Schneider AB.Radioiodine-induced thyroid cancer: Studies in the aftermath of the accident at Chernobyl. Trends Endocrinol Metab 1998; 9: 87-94.). It is very important to identify risk factors for thyroid cancer and use them to establish a prevention system for thyroid cancer. Moreover, since thyroid cancer is detected early and has a very high survival rate, it is also important to establish a method for early and accurate diagnosis. Currently screening for thyroid disease uses ultrasound, and no special preventive method is known.
여러 갑상선 호르몬들이 유방암이나 갑상선암의 증식(proliferation)에 관여한다는 연구들이 보고되고 있다. 유방암과 같은 호르몬-관련 종양에서 16α-히드록시에스트론(16α-hydroxyestrone, 16α-OHE1)의 종양 증식 (proliferative effect)과 2-히드록시에스트론(2-hydroxyestrone, 2-OHE1)의 종양 억제(anti-proliferative effect)에 대해서 연구되어졌다(Bradlow H, et al. Role of the estrogen receptor in the action of organochlorine pesticides on estrogen metabolism in human breast cancer cell lines. Sci Total Environ 1997;208:9-14). 또한, 2-OHE1와 16α-OHE1의 비율이 유방암의 바이오마커(biomarker)로 연구되어졌다 (Meilhan E, et al. Do urinary estrogen metabolites predict breast cancer? Follow up of the Guernsey III cohort. Br Cancer J 1998;78(9):1250-5; Telang N, et al. Estradiol metabolism: an endocrine biomarker for modulation of human mammary carcinogenesis. Environ Health Persp 1997;105:559-64). 2-OHE1와 16α-OHE1의 비율과 갑상선 질병과의 관계도 연구되어지고 있다 (Chan EK, et al. A hormonal association between estrogen metabolism and proliferative thyroid disease. Otolaryngol Head Neck Surg. 2006 Jun;134(6):893-900). 2-메톡시에스트라디올(2-MeO-E2)이 갑상선암 세포에서 종양 억제 및 사멸(anti-proliferative and apoptotic effect)을 나타낸다는 연구가 이루어졌다(Roswall P, et al. 2-methoxyestradiol induces apoptosis in cultured human anaplastic thyroid carcinoma cells. Thyroid. 2006 Feb;16(2):143-50). 일반적으로 16α-OHE1이 암의 증식(proliferation)에 관여하므로 위험인자로서 인정되고 있다. 그러나 2-OHE1와 16α-OHE1의 비율이 바이오마커가 될 수 없다는 연구결과도 있다 (McDougal A, Safe S Induction of 16α/2-Hydroxyestrone Metabolite Ratios in MCF-7 Cells by Pesticides, Carcinogens, and Antiestrogens Does Not Predict Mammary Carcinogens Environ Health Persp 1998; 106: 203-206). Several studies have reported that thyroid hormones are involved in the proliferation of breast cancer or thyroid cancer. Tumor proliferative effect of 16α-hydroxyestrone (16α-OHE1) and tumor suppression of 2-hydroxyestrone (2-OHE1) in hormone-related tumors such as breast cancer proliferative effect) (Bradlow H, et al. Role of the estrogen receptor in the action of organochlorine pesticides on estrogen metabolism in human breast cancer cell lines.Sci Total Environ 1997; 208: 9-14). In addition, the ratio of 2-OHE1 and 16α-OHE1 has been studied as a biomarker of breast cancer (Meilhan E, et al. Do urinary estrogen metabolites predict breast cancer? Follow up of the Guernsey III cohort.Br Cancer J 1998 78 (9): 1250-5; Telang N, et al. Estradiol metabolism: an endocrine biomarker for modulation of human mammary carcinogenesis. Environ Health Persp 1997; 105: 559-64). The relationship between the ratio of 2-OHE1 and 16α-OHE1 and thyroid disease has also been studied (Chan EK, et al. A hormonal association between estrogen metabolism and proliferative thyroid disease.Otolaryngol Head Neck Surg. 2006 Jun; 134 (6) : 893-900). Studies have shown that 2-methoxyestradiol (2-MeO-E2) exhibits anti-proliferative and apoptotic effects in thyroid cancer cells (Roswall P, et al. 2-methoxyestradiol induces apoptosis in cultured) human anaplastic thyroid carcinoma cells.Thyroid. 2006 Feb; 16 (2): 143-50). In general, 16α-OHE1 is recognized as a risk factor because it is involved in cancer proliferation. However, some studies have shown that the ratio of 2-OHE1 and 16α-OHE1 cannot be a biomarker (McDougal A, Safe S Induction of 16α / 2-Hydroxyestrone Metabolite Ratios in MCF-7 Cells by Pesticides, Carcinogens, and Antiestrogens Does Not Predict Mammary Carcinogens Environ Health Persp 1998; 106: 203-206).
즉, 극히 일부 호르몬 농도 또는 비율과 갑상선암의 진행과의 관계가 제시되기는 했으나 그 결과에 있어서 일관성이 없었으므로, 갑상선암을 진단할 수 있는 체계적인 연구는 확립되어 있지 않은 상태이다.In other words, although the relationship between some hormone concentrations or ratios and the progression of thyroid cancer has been suggested, the results were inconsistent, and no systematic studies have been established to diagnose thyroid cancer.
이에 본 발명자들은 신뢰성 있게 갑상선암의 질병여부 및 그 진행정도를 진단할 수 있는 방법에 대해 연구한 결과, 정상인에 비해 갑상선암 환자의 신체 샘플 중에서 그 평균수치가 유의적으로 증가하는 호르몬군을 확립하였으며, 그 호르몬 군을 이용하여 신뢰성 있게 갑상선암을 진단할 수 있는 방법을 개발하여 본 발명을 완성하게 되었다.Accordingly, the present inventors have reliably studied the thyroid cancer disease and its progression method, and as a result, we established a hormone group that significantly increases the mean value in the body samples of thyroid cancer patients compared to normal people, The present invention has been completed by developing a method for reliably diagnosing thyroid cancer using the hormone group.
따라서, 본 발명의 목적은 신체 샘플 중에서 측정된 호르몬군의 농도를 이용하여 갑상선암을 신뢰성 있게 진단하는 갑상선암 진단방법을 제공하는 것이다.Accordingly, an object of the present invention is to provide a thyroid cancer diagnosis method for reliably diagnosing thyroid cancer using concentrations of hormone groups measured in body samples.
본 발명의 다른 목적은 신체 샘플 중에서 측정된 호르몬군의 농도를 이용하여 갑상선암을 신뢰성 있게 진단할 수 있는 갑상선암 진단장치를 제공하는 것이다.Another object of the present invention is to provide a thyroid cancer diagnosis apparatus capable of reliably diagnosing thyroid cancer using concentrations of hormone groups measured in body samples.
상기 목적을 달성하기 위하여, 본 발명의 일 측면은 In order to achieve the above object, an aspect of the present invention
정상군과 갑상선암 환자군 각각의 모집단의 신체 샘플로부터 측정된 2-히드록시에스트론(2-OH-E1), 2-히드록시에스트라디올(2-OH-E2), 2-메톡시에스트론(2-MeO-E1), 2-메톡시에스트라디올(2-MeO-E2), 및 2-메톡시에스트라디올-3-메틸에테르(2-MeO-E2-3-메틸에테르)로 구성된 군에서 선택된 3 가지 이상의 호르몬 농도를 데이터로 하여 얻어진 통계치를, 진단 대상의 샘플값과 비교하여 갑상선암 여부 또는 진행정도를 판단하는 갑상선암 진단방법을 제공한다. 2-hydroxyestrone (2-OH-E1), 2-hydroxyestradiol (2-OH-E2), 2-methoxyestrone (2-MeO) measured from body samples of the populations of the normal and thyroid cancer patient groups, respectively. At least three selected from the group consisting of -E1), 2-methoxyestradiol (2-MeO-E2), and 2-methoxyestradiol-3-methylether (2-MeO-E2-3-methylether) Provided is a thyroid cancer diagnosis method for determining whether or not thyroid cancer progresses by comparing statistical values obtained by using hormone concentrations as data.
또한, 본 발명의 다른 측면은 In addition, another aspect of the present invention
갑상선암 진단에 필요한 정보를 제공하기 위하여, 정상군과 갑상선암 환자군 각각의 모집단의 신체 샘플로부터 측정된 2-히드록시에스트론(2-OH-E1), 2-히드록시에스트라디올(2-OH-E2), 2-메톡시에스트론(2-MeO-E1), 2-메톡시에스트라디올(2-MeO-E2), 및 2-메톡시에스트라디올-3-메틸에테르(2-MeO-E2-3-메틸에테르)로 구성된 군에서 선택된 3 가지 이상의 호르몬 농도를 데이터로 하여 얻어진 통계치를, 진단 대상의 샘플값과 비교분석하는 방법을 제공한다.2-hydroxyestron (2-OH-E1), 2-hydroxyestradiol (2-OH-E2) measured from body samples from populations of normal and thyroid cancer patient groups, respectively, to provide the information needed to diagnose thyroid cancer , 2-methoxy estrone (2-MeO-E1), 2-methoxy estradiol (2-MeO-E2), and 2-methoxy estradiol-3-methyl ether (2-MeO-E2-3-methyl A method for comparing and analyzing the statistical values obtained by using three or more hormone concentrations selected from the group consisting of ether) as a sample value of a diagnosis target.
본 발명의 또 다른 측면은Another aspect of the invention
진단 대상의 신체 샘플로부터 측정된 호르몬 농도를 입력하는 호르몬 농도 입력부;Hormone concentration input unit for inputting the hormone concentration measured from the body sample of the diagnosis object;
정상군과 갑상선암 환자군 각각의 모집단의 신체 샘플로부터 측정된 2-히드록시에스트론(2-OH-E1), 2-히드록시에스트라디올(2-OH-E2), 2-메톡시에스트론(2-MeO-E1), 2-메톡시에스트라디올(2-MeO-E2), 및 2-메톡시에스트라디올-3-메틸에테르(2-MeO-E2-3-메틸에테르)로 구성된 군에서 선택된 3 가지 이상의 호르몬 농도를 데이터로 하여 얻어진 통계치가 저장되어 있고, 상기 입력부를 통해 입력된 상기 3 가지 이상의 호르몬 농도를 이용하여 상기 통계치에 해당하는 기초로 진단대상의 샘플값을 계산하고, 그 진단대상의 샘플값을 상기 저장된 통계치와 비교하여 갑상선암 여부 또는 진행 정도를 판단하는 진단 프로그램 모듈; 및 2-hydroxyestrone (2-OH-E1), 2-hydroxyestradiol (2-OH-E2), 2-methoxyestrone (2-MeO) measured from body samples of the populations of the normal and thyroid cancer patient groups, respectively. At least three selected from the group consisting of -E1), 2-methoxyestradiol (2-MeO-E2), and 2-methoxyestradiol-3-methylether (2-MeO-E2-3-methylether) Statistical values obtained by using hormone concentrations as data are stored, and the sample values of the diagnosis subjects are calculated based on the statistical values using the three or more hormone concentrations input through the input unit, and the sample values of the diagnosis subjects. A diagnostic program module for determining whether or not the progression of thyroid cancer by comparing the stored statistics with And
상기 진단 결과를 출력하는 출력부를 포함하는 컴퓨터 시스템인 갑상선암 진단장치를 제공한다. Provided is a thyroid cancer diagnosis device which is a computer system including an output unit for outputting the diagnosis result.
이하, 본 발명을 보다 상세하게 설명한다. Hereinafter, the present invention will be described in more detail.
본 발명에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 본 발명의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한 본 명세서에는 바람직한 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 발명의 범주에 포함된다. 본 명세서에 참고문헌으로 기재되는 모든 간행물의 내용은 본 발명에 전체가 참고로 통합된다. All technical terms used in the present invention, unless defined otherwise, are used in the meaning as commonly understood by those skilled in the art in the related field of the present invention. Also described herein are preferred methods or samples, but similar or equivalent ones are within the scope of the present invention. The contents of all publications described herein by reference are incorporated herein by reference in their entirety.
본 발명자들은 갑상선암 질병을 신뢰성 있게 진단할 수 있는 방법을 연구한 결과, 갑상선암 환자군의 신체 샘플에서 정상군에 비해 그 평균값이 유의적으로 증가하는 호르몬군을 최초로 확립하였으며, 그 호르몬군을 이용하여 통계학적으로 갑상선암의 여부 및 진행정도를 결정할 수 있는 방법을 확립하였다. 구체적으로는, 모집단의 갑상선암 환자군 및 정상군의 신체 샘플로부터 안드로겐 및 에스트로겐 대사 경로상의 18 가지의 호르몬 농도를 측정한 다음 각각의 평균값을 계산한 결과, 통계적으로 정상군에 비해 갑상선암 환자군에서 평균값이 현저히 증가하는 5 가지 호르몬군, 2-히드록시에스트론(2-OH-E1), 2-히드록시에스트라디올(2-OH-E2), 2-메톡시에스트론(2-MeO-E1), 2-메톡시에스트라디올(2-MeO-E2), 및 2-메톡시에스트라디올-3-메틸에테르(2-MeO-E2-3-메틸에테르)을 발견하였다. 그 호르몬군의 각각의 호르몬에 대해 갑상선암 환자군 및 정상군 각각의 피어슨(pearson) 상관계수를 계산하고, 정상군과 갑상선암 환자군의 피어슨 상관계수를 비교한 결과, 상기 호르몬군의 모두에서 정상군과 갑상선암 환자군의 피어슨 상관계수가 현저한 차이가 있음을 보여주어 이러한 호르몬군의 농도변화를 이용한 갑상선암 진단법이 신뢰성이 있음을 확인하였다. 다만, 상기 5가지 호르몬군은 정상군에 대한 갑상선암 환자의 농도 변화에 있어서 변동성이 매우 크므로 단순히 그 호르몬 농도의 절대값의 변화만을 비교할 경우 위양성(false positive) 결과의 증가를 나타낼 우려가 있으며, 상기 호르몬군 중에서 2개 이하의 호르몬만을 비교할 경우 신뢰성 있게 갑상선암을 진단하기 어려운 것으로 나타났다. 따라서, 상기 5 가지 호르몬군중 3 가지 이상의 호르몬 농도를 데이터로 하여 얻어진 통계치를, 진단대상의 신체 샘플의 상기 3 가지 이상의 호르몬 농도의 해당 값(즉, 진단 대상의 샘플값)과 비교하여 갑상선암 여부 또는 진행정도를 결정하는 방법을 착안하였다.The present inventors studied a method for reliably diagnosing thyroid cancer disease, and as a result, for the first time, we established a hormone group in which the mean value of the thyroid cancer patient group was significantly increased compared to the normal group. We have established a methodology to determine the extent and progression of thyroid cancer. Specifically, 18 hormone levels on androgen and estrogen metabolic pathways were measured from thyroid cancer patients and normal body samples of the population, and then the average values were calculated. The mean values were significantly higher in the thyroid cancer patients group than in the normal group. 5 increasing hormonal groups, 2-hydroxyestrone (2-OH-E1), 2-hydroxyestradiol (2-OH-E2), 2-methoxyestrone (2-MeO-E1), 2-meth Toxyestradiol (2-MeO-E2), and 2-methoxyestradiol-3-methylether (2-MeO-E2-3-methylether) were found. Pearson correlation coefficients of the thyroid cancer patient group and the normal group were calculated for each hormone of the hormone group, and the Pearson correlation coefficients of the normal group and the thyroid cancer patient group were compared. Pearson's correlation coefficients in the patient group showed significant differences, indicating that the thyroid cancer diagnosis using the hormonal changes was reliable. However, since the five hormone groups have very high variability in changes in the concentration of thyroid cancer patients with respect to the normal group, there may be an increase in false positive results when only comparing the absolute value of the hormone concentration. When comparing only two or less hormones among the hormone groups, it was difficult to reliably diagnose thyroid cancer. Accordingly, the statistics obtained by using three or more hormone concentrations among the five hormone groups as data are compared with the corresponding values of the three or more hormone concentrations (ie, sample values for diagnosis) of the body sample to be diagnosed, or The method of determining the progress was devised.
따라서, 본 발명의 일 측면은 Thus, one aspect of the present invention
정상군과 갑상선암 환자군 각각의 모집단의 신체 샘플로부터 측정된 2-히드록시에스트론(2-OH-E1), 2-히드록시에스트라디올(2-OH-E2), 2-메톡시에스트론(2-MeO-E1), 2-메톡시에스트라디올(2-MeO-E2), 및 2-메톡시에스트라디올-3-메틸에테르(2-MeO-E2-3-메틸에테르)로 구성된 군에서 선택된 3 가지 이상의 호르몬 농도를 데이터로 하여 얻어진 통계치를, 진단 대상의 샘플값과 비교하여 갑상선암 여부 또는 진행정도를 판단하는 갑상선암 진단방법을 제공한다.2-hydroxyestrone (2-OH-E1), 2-hydroxyestradiol (2-OH-E2), 2-methoxyestrone (2-MeO) measured from body samples of the populations of the normal and thyroid cancer patient groups, respectively. At least three selected from the group consisting of -E1), 2-methoxyestradiol (2-MeO-E2), and 2-methoxyestradiol-3-methylether (2-MeO-E2-3-methylether) Provided is a thyroid cancer diagnosis method for determining whether or not thyroid cancer progresses by comparing statistical values obtained by using hormone concentrations as data.
또한, 본 발명의 다른 측면은 In addition, another aspect of the present invention
갑상선암 진단에 필요한 정보를 제공하기 위하여, 정상군과 갑상선암 환자군 각각의 모집단의 신체 샘플로부터 측정된 2-히드록시에스트론(2-OH-E1), 2-히드록시에스트라디올(2-OH-E2), 2-메톡시에스트론(2-MeO-E1), 2-메톡시에스트라디올(2-MeO-E2), 및 2-메톡시에스트라디올-3-메틸에테르(2-MeO-E2-3-메틸에테르)로 구성된 군에서 선택된 3 가지 이상의 호르몬 농도를 데이터로 하여 얻어진 통계치를, 진단 대상의 샘플값과 비교분석하는 방법을 제공한다.2-hydroxyestron (2-OH-E1), 2-hydroxyestradiol (2-OH-E2) measured from body samples from populations of normal and thyroid cancer patient groups, respectively, to provide the information needed to diagnose thyroid cancer , 2-methoxy estrone (2-MeO-E1), 2-methoxy estradiol (2-MeO-E2), and 2-methoxy estradiol-3-methyl ether (2-MeO-E2-3-methyl A method for comparing and analyzing the statistical values obtained by using three or more hormone concentrations selected from the group consisting of ether) as a sample value of a diagnosis target.
상기 "3가지 이상의 호르몬 농도를 데이터로 하여 얻어진 통계치"란, 정상군과 갑상선암 환자군 각각의 모집단의 신체샘플로부터 측정된 3 가지 이상의 호르몬 농도로부터 임의의 통계학적 방법에 의해 얻어진 통계치로서, 그 통계치를 진단 대상의 샘플값과 비교하여 갑상선암의 여부 또는 진행정도를 판단할 수 있는 통계치를 말한다. 상기 "진단 대상의 샘플값"이란 진단하고자 하는 대상의 신체 샘플로부터 측정된 상기 3가지 이상의 호르몬 농도의 상기 통계치에 해당하는 값을 말한다.The "statistics obtained by using three or more hormone concentrations as data" means statistical values obtained by any statistical method from three or more hormone concentrations measured from body samples of the populations of the normal group and the thyroid cancer patient group, respectively. It is a statistical value that can determine the progress or progression of thyroid cancer compared to the sample value of the diagnosis target. The "sample value of the diagnosis subject" refers to a value corresponding to the statistical value of the three or more hormone concentrations measured from a body sample of the subject to be diagnosed.
상기 "3 가지 이상의 호르몬 농도를 데이터로 하여 얻어진 통계치"는 특별히 한정되는 것은 아니나, 바람직하게는 다중회귀분석법을 이용하여 얻어진 회귀식이다. 구체적으로는, 상기 정상군과 갑상선암 환자군 각각의 모집단의 신체 샘플로부터 측정된 3 가지 이상의 호르몬 농도를 데이터로 하고 정상군과 갑상선암 환자군의 일부 또는 전부에 대해 질병의 진행 순서를 임의로 정한 가능한 모든 경우의 수에 대해 다중회귀분석법에 의해 얻어지는 회귀식을 갑상선 질병지수의 식으로 하며, 상기 회귀식을 상기 3 가지 이상의 호르몬 농도를 데이터로 하여 얻어진 통계치로서 이용할 수 있다. 상기 회귀식은 다중회귀분석법 결과 결정계수(r2)가 0.6 이상이여야 하며, 가장 높은 회귀식인 것인 바람직하다. 상기 갑상선 질병지수의 식에 진단 대상의 신체 샘플의 상기 3 가지 이상의 호르몬 농도를 대입하여 얻어진 갑상선 질병지수(즉, 상기 진단대상의 샘플값)에 따라 갑상선암 여부 또는 진행정도를 진단할 수 있다. 보다 구체적으로는, 상기 다중회귀분석법에 의해 회귀식을 결정할 때, 모집단의 데이터에 기초하여 갑상선암인 경우의 갑상선 질병지수 값, 정상인 경우의 갑상선 질병지수 값, 정상에서 갑상선암으로의 이행단계인 경우의 갑상선 질병지수 값을 기준값으로서 설정하고, 상기 회귀식에 진단대상의 신체샘플의 상기 3 가지 이상의 호르몬 농도를 대입하여 얻어진 갑상선 질병지수(즉, 진단대상의 샘플값)가 상기 기준값 중 어느 영역에 속하는 지를 판단하여 갑상선암의 여부 및 진행정도를 결정할 수 있다. The "statistic obtained by using three or more hormone concentrations as data" is not particularly limited, but is preferably a regression equation obtained using multiple regression analysis. Specifically, in all possible cases where data of three or more hormone concentrations measured from the body samples of the respective populations of the normal group and the thyroid cancer patient group are used, and the order of disease progression is arbitrarily determined for some or all of the normal group and the thyroid cancer patient group. A regression equation obtained by multiple regression analysis on numbers can be used as a thyroid disease index, and the regression equation can be used as a statistical value obtained by using the three or more hormone concentrations as data. The regression equation has a coefficient of determination (r 2 ) of 0.6 or more as a result of multiple regression analysis, it is preferred that the highest regression equation. According to the thyroid disease index (ie, the sample value of the diagnosis target) obtained by substituting the three or more hormone concentrations of the body sample to be diagnosed into the expression of the thyroid disease index, it is possible to diagnose whether or not the progression of thyroid cancer. More specifically, when determining the regression equation by the multiple regression analysis, the thyroid disease index value in the case of thyroid cancer, the thyroid disease index value in the case of normal, the transition stage from normal to thyroid cancer based on the population data The thyroid disease index value (ie, a sample value for diagnosis) obtained by setting the thyroid disease index value as a reference value and substituting the three or more hormone concentrations of the body sample to be diagnosed into the regression formula belongs to any region of the reference value. It can determine whether thyroid cancer is present and how far it progresses.
상기 다중회귀분석법에서 정상군 및 갑상선암 환자군은 이진 데이터로서 이용하면 상기 회귀식을 얻을 수 없으며, 갑상선암 질병군과 정상군의 전부 또는 일부를 각각의 개체에 대해 임의로 가능한 모든 질병진행 순서를 배치하고 모든 경우의 대해서 다중회귀분석법을 수행하여, 상기 회귀식을 얻을 수 있다. In the multiple regression analysis, the normal group and the thyroid cancer patient group cannot use the binary data to obtain the regression equation, and all or part of the thyroid cancer disease group and the normal group are arranged at random in all possible cases of disease progression for each individual, and in all cases. The regression equation can be obtained by performing multiple regression analysis on.
상기 신체 샘플은 상기 3가지 이상의 호르몬 농도를 측정할 수 있는 임의의 신체 샘플일 수 있으며, 예를 들어 뇨, 혈액, 또는 타액이 이용될 수 있다. 바람직하게는, 뇨 또는 혈액 중의 혈청이 이용될 수 있다.The body sample can be any body sample capable of measuring the three or more hormone concentrations, for example urine, blood, or saliva can be used. Preferably, urine or serum in blood may be used.
상기 호르몬 농도 측정방법은 당해 기술분야에 공지되어 있는 임의의 방법에 의해 수행할 수 있으며, 예를 들어 GC-MS-SIM(Gas Chromatography- Mass Spectrometry-Selected Ion-Monitorng), HPLC (High-performance liquid chromatography), EIA (competitive solid-phase enzyme immunoassay) 등의 방법에 의해 측정할 수 있다.The hormone concentration measurement method may be performed by any method known in the art, for example, GC-MS-SIM (Gas Chromatography- Mass Spectrometry-Selected Ion-Monitorng), HPLC (High-performance liquid) chromatography, and EIA (competitive solid-phase enzyme immunoassay).
상기 갑상선암 진단방법에서 3 가지 이상의 호르몬 농도는 4 가지 이상의 호르몬 농도인 것이 더욱 바람직하다. 상기 통계치 또는 갑상선 질병지수를 획득하기 위한 데이터로서 4개 이상의 호르몬 농도를 사용하면 갑상선암 진단의 신뢰성을 더욱 높일 수 있다. 상기 4개 이상의 호르몬은 예를 들어, 2-히드록시에스트론, 2-히드록시에스트라디올, 2-메톡시에스트라디올, 및 2-메톡시에스트라디올-3-메틸에테르를 포함할 수 있다. In the thyroid cancer diagnosis method, the three or more hormone concentrations are more preferably four or more hormone concentrations. The use of four or more hormone concentrations as data for obtaining the statistics or the thyroid disease index can further increase the reliability of thyroid cancer diagnosis. The four or more hormones may include, for example, 2-hydroxyestrone, 2-hydroxyestradiol, 2-methoxyestradiol, and 2-methoxyestradiol-3-methylether.
본 발명의 일 구현예에 따르면, 정상군과 갑상선암 환자군 각각의 모집단의 신체 샘플로부터 측정된 4 가지 이상의 호르몬 농도를 데이터로 하여 다중회귀분석법에 의해 얻어진 회귀식은 다음과 같다:According to one embodiment of the present invention, a regression equation obtained by multiple regression analysis using at least four hormone concentrations measured from body samples of a population of each of the normal and thyroid cancer patient groups is as follows:
갑상선 질병지수 (TDI) = 0.0153x2-MeO-E2-3-메틸에테르 + 0.0874x2-MeO-E2/2-OH-E2 - 2.2571x2-MeO-E2-3-메틸에테르/2-OH-E1 + 0.5649Thyroid Disease Index (TDI) = 0.0153x2-MeO-E2-3-methylether + 0.0874x2-MeO-E2 / 2-OH-E2-2.2571x2-MeO-E2-3-methylether / 2-OH-E1 + 0.5649
상기 갑상선 질병지수 식에서 질병지수가 0 에서 0.8 사이는 정상군이며, 1.0 이상은 갑상선암 환자군이며. 0.8 내지 1.0 은 경계지역으로서 갑상선암 위험군이다. In the above thyroid disease index equation, the disease index is between 0 and 0.8, and the thyroid cancer patient group is 1.0 or more. 0.8 to 1.0 is a borderline thyroid cancer risk group.
상기 갑상선암 진단방법은 갑상선암 진단장치로서 구현되어, 진단대상의 신체 샘플에서 측정된 호르몬 농도의 입력에 의해 갑상선암 여부 및 진행정도를 알 수 있는 갑상선암 진단장치를 제공할 수 있다.The thyroid cancer diagnosis method may be implemented as a thyroid cancer diagnosis apparatus, and may provide a thyroid cancer diagnosis apparatus capable of knowing whether or not the thyroid cancer progresses by inputting a hormone concentration measured in a body sample to be diagnosed.
따라서, 본 발명의 또 다른 일 측면은Therefore, another aspect of the present invention
진단 대상의 신체 샘플로부터 측정된 호르몬 농도를 입력하는 호르몬 농도 입력부;Hormone concentration input unit for inputting the hormone concentration measured from the body sample of the diagnosis object;
정상군과 갑상선암 환자군 각각의 모집단의 신체 샘플로부터 측정된 2-히드록시에스트론(2-OH-E1), 2-히드록시에스트라디올(2-OH-E2), 2-메톡시에스트론(2-MeO-E1), 2-메톡시에스트라디올(2-MeO-E2), 및 2-메톡시에스트라디올-3-메틸에테르(2-MeO-E2-3-메틸에테르)로 구성된 군에서 선택된 3 가지 이상의 호르몬 농도를 데이터로 하여 얻어진 통계치가 저장되어 있고, 상기 입력부를 통해 입력된 상기 3 가지 이상의 호르몬 농도를 이용하여 상기 통계치에 해당하는 기초로 진단대상의 샘플값을 계산하고, 그 진단대상의 샘플값을 상기 저장된 통계치와 비교하여 갑상선암 여부 또는 진행 정도를 판단하는 진단 프로그램 모듈; 및 2-hydroxyestrone (2-OH-E1), 2-hydroxyestradiol (2-OH-E2), 2-methoxyestrone (2-MeO) measured from body samples of the populations of the normal and thyroid cancer patient groups, respectively. At least three selected from the group consisting of -E1), 2-methoxyestradiol (2-MeO-E2), and 2-methoxyestradiol-3-methylether (2-MeO-E2-3-methylether) Statistical values obtained by using hormone concentrations as data are stored, and the sample values of the diagnosis subjects are calculated based on the statistical values using the three or more hormone concentrations input through the input unit, and the sample values of the diagnosis subjects. A diagnostic program module for determining whether or not the progression of thyroid cancer by comparing the stored statistics with And
상기 진단 결과를 출력하는 출력부를 포함하는 컴퓨터 시스템인 갑상선암 진단장치를 제공한다. Provided is a thyroid cancer diagnosis device which is a computer system including an output unit for outputting the diagnosis result.
상기 진단 프로그램 모듈은 상기 정상군과 갑상선암 환자군 각각의 모집단의 신체샘플로부터 측정된 3 가지 이상의 호르몬 농도를 데이터로 하여 다중회귀분석법에 의해 얻어진 회귀식을 갑상선 질병지수의 식으로서 저장하고 있고, 상기 입력부를 통해 입력된 진단 대상의 신체 샘플의 상기 3 가지 이상의 호르몬 농도를 상기 저장된 갑상선 질병지수의 식에 대입하여 얻어진 갑상선 질병지수에 따라 갑상선암 여부 또는 진행정도를 판단하는 프로그램을 포함할 수 있다. 상기 프로그램은 앞서 설명한 본 발명의 일 측면에 따른 갑상선암 진단방법을 수행하는 방식으로 설계될 수 있고, 상기 본 발명의 일 측면에 따른 갑상선암 진단방법의 모든 가능한 구현예를 수행할 수 있는 방식으로 설계될 수 있다. 이를 수행하기 위한 상기 진단 프로그램 모듈이 구비해야 하는 프로그램은 당해 컴퓨터 프로그램 분야에서 통상의 지식을 가진 자가 본 명세서의 기재 및 컴퓨터 프로그램 분야에 공지된 지식을 이용하여 설계할 수 있음이 자명하다. The diagnostic program module stores a regression equation obtained by multiple regression analysis as a formula of thyroid disease index using at least three hormone concentrations measured from body samples of the populations of the normal group and the thyroid cancer patient group as data. It may include a program for determining whether or not the progression of thyroid cancer according to the thyroid disease index obtained by substituting the three or more hormone concentrations of the body sample of the diagnosis subject input through the formula into the formula of the stored thyroid disease index. The program may be designed in such a manner as to perform a thyroid cancer diagnostic method according to an aspect of the present invention described above, and may be designed in such a manner as to perform all possible embodiments of the thyroid cancer diagnostic method according to an aspect of the present invention. Can be. It is apparent that the program that the diagnostic program module should have to perform this design can be designed by those skilled in the computer program field using the knowledge known in the present specification and the computer program field.
상기 갑상선암 진단장치는 호르몬 농도 입력부에 진단 대상의 신체 샘플로부터 측정된 3가지 이상의 호르몬 농도의 입력에 의해, 상기 진단 프로그램 모듈이 자동적으로 작동되어 갑상선암 진단 결과가 출력부를 통해 자동적으로 출력될 수 있도록 할 수도 있으며, 별도의 수동적인 동작에 의해 상기 진단 프로그램 모듈의 작동 및 진단결과의 출력이 이루어지도록 할 수도 있다. The thyroid cancer diagnosis device may automatically activate the diagnostic program module by outputting three or more hormone concentrations measured from a body sample of a diagnosis target to a hormone concentration input unit so that a thyroid cancer diagnosis result may be automatically output through an output unit. Alternatively, the operation of the diagnostic program module and the output of the diagnosis result may be performed by a separate manual operation.
상기 진단 대상의 신체 샘플로부터 측정된 3가지 이상의 호르몬 농도의 입력은 별도로 측정장치에 의해 측정한 다음 얻어진 호르몬 농도를 입력할 수도 있으나, 상기 갑상선암 진단장치가 신체 샘플로부터 호르몬 농도를 측정하기 위한 호르몬 농도 측정기를 더 구비할 수도 있다. 즉, 상기 진단장치는 진단대상의 신체샘플로부터 호르몬 농도를 측정하기 위한 호르몬 농도 측정기를 더 구비하고, 그 호르몬 농도 측정기는 상기 호르몬 농도 입력부에 연결되어 호르몬 농도 측정기에 의해 측정된 호르몬 농도가 자동입력 되도록 할 수 있다. 상기 호르몬 농도 측정기는 상기 5 가지 호르몬 농도를 측정할 수 있는 임의의 측정기일 수 있으며, 예를 들어 GC-MS-SIM 장치(Gas Chromatography-Mass Spectrometry-Selected Ion-Monitorng), HPLC (High-performance liquid chromatography) 장치, EIA(competitive solid-phase enzyme immunoassay) 일 수 있다.The input of the three or more hormone concentrations measured from the body sample to be diagnosed may be inputted separately after measuring by a measuring device, but the hormone concentration for the thyroid cancer diagnostic device to measure the hormone concentration from the body sample. You may further comprise a measuring instrument. That is, the diagnostic apparatus further includes a hormone concentration measuring device for measuring hormone concentration from a body sample of the diagnosis target, and the hormone concentration measuring device is connected to the hormone concentration input unit so that the hormone concentration measured by the hormone concentration measuring device is automatically input. You can do that. The hormone concentration meter may be any meter capable of measuring the five hormone concentrations, for example, a GC-MS-SIM device (Gas Chromatography-Mass Spectrometry-Selected Ion-Monitorng), HPLC (High-performance liquid) chromatography, an EIA (competitive solid-phase enzyme immunoassay).
본 발명에 따른 갑상선암 진단방법 및 진단장치는 진단대상의 신체 샘플 중의 상기 5가지 호르몬 중 3 이상의 호르몬 농도를 측정함으로써 갑상선암의 여부 및 진행정도를 진단할 수 있다. 또한, 종래 초음파에 의한 영상으로 진단하는 방법에 비해, 혈액학적 변화를 측정함으로서 갑상선암을 진단할 수 있으므로 보다 조기에 갑상선암을 진단할 수 있다. 또한, 갑상선암 발병예측확률을 계산해 냄으로써 갑상선암을 예방하는데 효과적이며 갑상선암에 의한 사망률을 감소시킬 것으로 예상된다. 따라서, 본 발명에 따른 갑상선암 진단방법 및 진단장치는 조기 진단이 중요한 갑상선암의 특성상 매우 획기적이라고 할 수 있다. The thyroid cancer diagnosis method and apparatus according to the present invention can diagnose the thyroid cancer and the progress of the thyroid cancer by measuring the hormone concentration of three or more of the five hormones in the body sample to be diagnosed. In addition, since thyroid cancer can be diagnosed by measuring hematological changes, the thyroid cancer can be diagnosed earlier. In addition, by calculating the probability of developing thyroid cancer, it is expected to be effective in preventing thyroid cancer and reduce mortality from thyroid cancer. Therefore, it can be said that the method and diagnostic apparatus for thyroid cancer according to the present invention is very innovative due to the characteristics of thyroid cancer in which early diagnosis is important.
도 1은 본 발명의 일 구현예에 따라 갑상선암 환자군 및 정상군의 모집단에서의 호르몬 농도를 측정하고 환자군 및 정상군을 이진 데이터로서 이용하여 다중회귀분석법에 의해 결정계수가 가장 높게 얻어진 회귀식을 갑상선 질병지수로 하고, 상기 회귀식이 얻어진 질병진행 순서에 따른 호르몬 농도 데이터 및 갑상선 질병지수를 나타낸 그래프이다.1 is a thyroid gland which measures the hormone concentration in a population of thyroid cancer patients and normal groups according to an embodiment of the present invention, and obtains the highest coefficient of determination by multiple regression analysis using the patient and normal groups as binary data. The disease index is a graph showing the hormone concentration data and the thyroid disease index according to the disease progression sequence in which the regression equation is obtained.
이하, 본 발명을 하기 실시예에 의해 더욱 구체적으로 설명한다. 그러나, 이들 실시예는 본 발명에 대한 이해를 돕기 위한 것일 뿐, 어떤 의미로든 본 발명의 범위가 이들에 의해 제한되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention is not limited by them in any sense.
실시예 1Example 1
(1) 데이터 측정 및 t-분석(1) data measurement and t-analysis
23 명의 갑상선암 환자와 20 명의 정상인의 소변을 GC-MS-SIM (Gas Chromatography-Mass Spectrometry-Selected Ion-Monitoring) 시스템(Hewlett-Packard GC-MS: 5890A GC model,5970B mass-selective detector, HP 59970C MS chemstation)을 사용하여서 안드로겐과 에스트로겐 대사경로상의 18가지의 대사체(metabolite) 호르몬에 대한 프로파일 데이터를 얻었다. The urine of 23 patients with thyroid cancer and 20 normal people was collected from a gas chromatograph-mass spectrometry-selected ion-monitoring (GC-MS-SIM) system (Hewlett-Packard GC-MS: 5890A GC model, 5970A mass-selective detector chemstation was used to obtain profile data for 18 metabolite hormones on the androgen and estrogen metabolic pathways.
갑상선암 환자의 정보는 하기 표 1에 정리하였다. 갑상선암 환자군 중 18명은 여성이고 5명은 남성이며 연령은 26 내지 60 세로 분포하였다. 이중 갑상선암 (thyroid cancer) 11명, 갑상선 종양 (thyroid tumor) 6명, 갑상선 종 (thyroid mass) 3명, 갑상선 유두 암 (thyroid papillary cancer) 1명, 갑상선암의 일종인 갑상선종 (Goiter) 1명이다. 하기 표에서 pre/post는 수술 전/후를 의미한다. Information on thyroid cancer patients is summarized in Table 1 below. Of the thyroid cancer patients, 18 were female, 5 were male, and their age ranged from 26 to 60 years. There are 11 thyroid cancers, 6 thyroid tumors, 3 thyroid masses, 1 thyroid papillary cancer, and 1 goiter. In the following table, pre / post means pre / post surgery.
[표 1] TABLE 1
갑상선암 환자 23명의 정보Information on 23 Patients with Thyroid Cancer
갑상선 질병의 위험 인자를 찾기 위해서 상기 측정된 호르몬 프로파일 데이터에 대해 t-test 분석을 수행하였다. t-test 결과를 하기 표 2에 정리하였다. T-test analysis was performed on the measured hormone profile data to find risk factors for thyroid disease. The t-test results are summarized in Table 2 below.
[표 2] TABLE 2
안드로겐과 에스트로겐 대사경로상의 18가지의 대사체 호르몬에 대한 t-test 결과T-test results for 18 metabolite hormones on androgen and estrogen metabolic pathways
상기 표 2의 분석 결과 2-히드록시에스트론(2-OH-E1), 2-히드록시에스트라디올(2-OH-E2), 2-메톡시에스트론(2-MeO-E1), 2-메톡시에스트라디올(2-MeO-E2), 및 2-메톡시에스트라디올-3-메틸에테르(2-MeO-E2-3-메틸에테르) 호르몬에서 t 값이 매우 높게 나타났으며, 정상군에 비해 갑상선암 환자군에서 호르몬 농도가 현저히 증가함을 확인할 수 있었다. 이로부터 정상군과 갑상선암 환자군의 상기 호르몬 값의 평균치가 유의적으로 현저한 차이가 있는 것으로 확인되었다.As a result of the analysis of Table 2, 2-hydroxyestrone (2-OH-E1), 2-hydroxyestradiol (2-OH-E2), 2-methoxyestrone (2-MeO-E1), 2-methoxy The estradiol (2-MeO-E2) and 2-methoxyestradiol-3-methylether (2-MeO-E2-3-methylether) hormones showed a very high t value, compared to the normal group. Hormone concentrations were significantly increased in the patient group. From this, it was confirmed that the mean value of the hormone value in the normal group and thyroid cancer patient group was significantly different.
(2) 피어슨 상관계수 계산(2) Calculation of Pearson's Correlation Coefficient
갑상선암 환자군과 정상군 각각에서의 상기 5개의 호르몬군에 대해 피어슨 상관계수(Pearson correlation matrix)를 계산하여 하기 표 3에 정리하였다. Pearson correlation coefficients were calculated for the five hormone groups in the thyroid cancer patient group and the normal group, respectively, and are summarized in Table 3 below.
상기 표 3에서의 결과와 같이 갑상선암 환자군과 정상군의 피어슨 상관계수의 차이는 질병이 진행됨에 따라서 호르몬 프로파일이 변함을 보여준다. As shown in Table 3, the difference in the Pearson's correlation coefficient between the thyroid cancer patient group and the normal group shows that the hormone profile changes as the disease progresses.
(3) 다중회귀분석(3) Multiple regression analysis
상기 5가지 호르몬 군을 이용하여 갑상선암 진단을 위한 갑상선 질병지수를 획득하기 위해 다중회귀분석법(Multiple Linear Regression, MLR)을 수행하였다. 갑상선암 질병 진행에 대한 데이터가 없기 때문에, 갑상선암 환자군과 정상군은 binary data로 되어 있다. 다중회귀분석법을 사용하기 위해서는 binary data의 변환이 필요하며, 데이터들의 질병 진행의 순서를 알 수 없었기 때문에 정상군은 0.2에서 0.7 사이의 값을 환자군은 1.2에서 1.9의 값을 갖도록 임의의 순서리스트를 작성하였다. 갑상선암 환자군에서 8 개 정상군에서 6 개의 샘플의 질병진행을 임의의 순서로 정하여서 총 29,030,400의 순서 리스트를 얻을 수 있었다. 이러한 모든 순서에 대하여서 다중회귀분석을 수행하였다. 가장 좋은 결과를 갖는, 즉 결졍계수 r2이 가장 큰 회귀식으로서 하기 식을 얻었으며, 상기 회귀식을 갑상선 질병지수(TDI)로서 명명하였다. Multiple linear regression (MLR) was performed to obtain the thyroid disease index for diagnosing thyroid cancer using the five hormone groups. Since there is no data on the progression of thyroid cancer disease, the thyroid cancer patient group and the normal group are binary data. In order to use the multiple regression analysis, binary data is required to be converted. Since the order of disease progression of the data is not known, the normal group has a random order list so that the patient group has a value between 0.2 and 0.7. Created. A total of 29,030,400 sequences were obtained by randomly assigning the disease progression of six samples from eight normal groups of thyroid cancer patients. All these sequences were subjected to multiple regression analysis. The following formula was obtained as the best regression equation with the best result, namely the coefficient of determination r 2 , and the regression equation was named TDI.
갑상선 질병지수 (TDI) = 0.0153 x 2-MeO-E2-3-메틸에테르 + 0.0874 x 2-MeO-E2/2-OH-E2 - 2.2571 x 2-MeO-E2-3-메틸에테르/2-OH-E1 + 0.5649 Thyroid Disease Index (TDI) = 0.0153 x 2-MeO-E2-3-methylether + 0.0874 x 2-MeO-E2 / 2-OH-E2-2.2571 x 2-MeO-E2-3-methylether / 2-OH -E1 + 0.5649
도 1에 상기 갑상선 질병지수식이 얻어진 질병진행 순서에 따른 호르몬 농도 데이터 및 갑상선 질병지수를 그래프로 나타내었다. In FIG. 1, the thyroid disease index and the hormone concentration data according to the disease progression sequence obtained are shown in a graph.
도 1에 나타낸 개별적인 호르몬 농도의 변화 추이를 살펴보면, 갑상선암의 진행에 따라서 호르몬 농도는 증가하는 것으로 나타났으나, 그 변동성이 너무 심한 것으로 나타났다. 따라서, 2 가지 이하의 호르몬 데이터로 갑상선 질병의 진행을 판단하기 힘들 것으로 보인다. Looking at the change in the individual hormone concentration shown in Figure 1, the hormone concentration was shown to increase with the progression of thyroid cancer, but the variability was too severe. Therefore, it is difficult to judge the progression of thyroid disease with two or less hormonal data.
도 1에 나타난 그래프에서 갑상선 질병지수 0 에서 0.8 사이는 정상군인 것으로 나타났으며, 지수 1.0 이상은 갑상선암 환자군인 것으로 나타났다. 지수 1.0 이하의 경계지역의 처음의 4명의 환자는 각각, 갑상선 종(thyroid mass)(0.8055), 갑상선 종(goiter)(0.8806), thyroid mass(수술전 갑상선암, 0.8951), thyroid mass (수술전 갑상선암, 0.9112)인 것으로 나타났다. 이러한 결과에 따르면, 상기 획득된 최적의 회귀식인 갑상선 질병지수식은 갑상선암의 진행 순서에 따라 그 값이 증가하는 것으로 확인되었으므로, 상기 회귀식에 따라 갑상선 질병을 분류할 수 있는 것으로 확인되었다. 따라서, 상기 얻어진 갑상선 질병지수식에 따라 얻어지는 갑상선 질병지수의 범위에 기초하여 갑성선암의 여부 및 갑상선암의 진행정도를 판단할 수 있으므로, 상기 갑상선 질병지수(TDI)는 갑상선암 진단의 좋은 도구가 됨을 알 수 있다. In the graph shown in FIG. 1, the thyroid disease index of 0 to 0.8 was found to be a normal group, and the index 1.0 or more was shown to be a thyroid cancer patient group. The first four patients at the borderline below the index 1.0 were thyroid mass (0.8055), goiter (0.8806), thyroid mass (preoperative thyroid cancer, 0.8951), and thyroid mass (preoperative thyroid cancer). , 0.9112). According to these results, it was confirmed that the optimal regression equation of the acquired thyroid disease index increases in accordance with the progression of thyroid cancer, so that the thyroid disease can be classified according to the regression equation. Therefore, it is possible to determine whether thyroid cancer and the progression of thyroid cancer based on the range of the thyroid disease index obtained according to the obtained thyroid disease index, it is understood that the thyroid disease index (TDI) is a good tool for diagnosis of thyroid cancer Can be.
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