Genetic Epidemiology

遗传流行病学

• 批准号: 7593159
• 负责人: ALISA GOLDSTEIN
• 金额: $ 97.49万
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593159
• 关键词: Adult; Age; Area; BRAF gene; Biological Markers; Blood; Boston; Brain Neoplasms; Breast Cancer Risk Factor; CDKN2A gene; Candidate Disease Gene; Case-Control Studies; Cells; Characteristics; Childhood Medulloblastomas; Chordoma; Chronic; Clear Cell; Collaborations; Condition; Core Facility; Country; DNA; DNA Resequencing; Data; Data Analyses; Denmark; Development; Diagnosis; Disease regression; Division of Cancer Epidemiology and Genetics; Duct (organ) structure; Dysplastic Nevus; ERBB2 gene; Eastern Europe; Embryo; Enrollment; Epidermal Growth Factor Receptor; Epithelial; Estrogens; European; Evaluation; Family; Family Cancer History; Family history of; First Degree Relative; Frequencies; General Hospitals; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Glioma; Goals; Hair; Hair Color; Hemorrhagic Thrombocythemia; High-Risk Cancer; Histocompatibility Testing; Hormonal; Hormones; Human; Hypoxia-Inducible Factor Pathway; Iceland; Immunohistochemistry; Incidence; Individual; Institution; Interview; Invasive; Investigation; Italy; Laboratories; Link; Lobular; Lymphoma; Malignant - descriptor; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of kidney; Maps; Massachusetts; Measures; Mediating; Medical; Melanocortin 1 Receptor; Melanocytic nevus; Metabolism; Methodology; Mitogen-Activated Protein Kinases; Molecular; Molecular Profiling; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mutation; Myelofibrosis; Neoplasm Metastasis; Neoplasms; Nevi and Melanomas; Noninfiltrating Intraductal Carcinoma; Normal tissue morphology; Oncogenes; Outcome; Parents; Pathway interactions; Patients; Pattern; Pigmentation physiologic function; Poland; Polishes; Polycythemia Vera; Population; Population Control; Population Study; Predisposition; Prevalence; Process; Questionnaires; Radiation Oncology; Rate; Receptor Gene; Registries; Regulation; Relative (related person); Relative Risks; Renal Cell Carcinoma; Renal carcinoma; Respiratory Tract Infections; Rest; Risk; Risk Estimate; Risk Factors; Role; Sample Size; Scandinavia; Second Primary Cancers; Siblings; Signal Transduction Pathway; Skeleton; Skin; Slide; Somatic Mutation; Staining method; Stains; Stem cells; Subgroup; Susceptibility Gene; Sweden; Techniques; Testing; Tissue Microarray; Tissue Sample; Tissues; Tumor Tissue; Universities; Variant; alpha-Melanocyte stimulating hormone; base; cancer risk; cancer type; carcinogenesis; case control; cdc Genes; disorder risk; genetic association; genetic epidemiology; genetic variant; hormone biosynthesis; human ESR1 protein; malignant breast neoplasm; medulloblastoma; melanoma; receptor; sex; telomere; tumor; tumorigenesis

Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. Questionnaire data, tumor, and DNA from a case-control study of 183 incident melanoma cases and 179 controls conducted in North-Eastern Italy were used to evaluate the melanocortin-1 receptor (MC1R) gene, the major regulator of pigmentation in humans, and somatic mutations of the BRAF oncogene, involved in the MAP-kinase pathway of signal transduction in melanomas. In subjects with melanoma arising on sun exposed areas of the body and with limited chronic solar damage, we found a strong association between MC1R germline variants and melanoma with somatic mutations in the BRAF oncogene. We plan to first verify this association and the role of potential modifiers in an independent population. Germline CDKN2A mutations have been observed in 20-40% of high-risk melanoma-prone families, however little is known about their prevalence in population-based cases and controls. Multiple MC1R variants have been associated with increased risk of melanoma. The Icelandic population has a high frequency of red hair and blond hair color subjects making it an ideal population to evaluate variation in MC1R.We resequenced the CDKN2A and MC1R genes in 703 registry-ascertained melanoma cases and 691 population-based controls from Iceland, a country in which the incidence of melanoma has increased rapidly. Evaluation of associations is in progress.One of the potential pathways that leads to the development of melanoma includes the loss of regulation of common melanocytic nevi, which acquire atypic or dysplastic characteristics that can further evolve in neoplasia. To study this pathway, we are currently collecting multiple tissue samples of normal skin, common melanocytic nevi, dysplastic nevi, melanoma and metastasis from melanoma from the same subjects from North-Eastern Italy. When the sample size reaches 100 subjects, we plan to study the expression and presence of mutations in multiple genes of the cell cycle, telomere, and transduction pathways in the serial tissue samples and germline DNA to explore the mechanisms involved in melanoma development through nevi.Relatives of 365 of the glioma cases from a DCEG comprehensive case-control study of adults with brain tumors were interviewed about personal/family medical history and other risk factors. Analyses to examine the risk of cancer among the first degree relatives compared to population controls have been completed. Examination of questionnaire data from a retrospective single institution study of childhood medulloblastoma showed little evidence for increased cancer risks among relatives of medulloblastoma patients.Chordoma is a rare primary malignant bone tumor that arises mainly in the axial skeleton from rests of embryonic notochordal stem cells that failed to undergo normal regression. We initiated a collaboration with the Department of Radiation Oncology, Massachusetts General Hospital, Boston, to try to identify chordoma families to help map and identify a chordoma susceptibility gene. The project involves obtaining personal and family medical history, buccal cells and slides of tumor tissue from the subgroup of patients most likely to have a genetic predisposition to chordoma: those diagnosed with chordoma <18 years. During the past year we completed enrollment of 45 chordoma patients. We are in the process of obtaining personal and family medical history, buccal cells and tumor tissue from them.In collaboration with Yale University Tissue Microarray (TMA) core facility, we have successfully built TMAs of 842 invasive tumors (TMA1) collected from the Polish Breast Cancer Study. We have immunohistochemically stained these TMAs for 18 molecular markers involved in hormone biosynthesis, metabolism, and receptor mediated pathways. Analyses of these markers suggest that risk factors for breast cancer may vary by molecular subtypes and by hormone pathways characterized by co-expression of the hormonal markers. We have also stained these arrays for four markers (ER-alpha, ER-beta, PR and HER2) using a newly developed Automated Quantitative Analysis (AQUA). Comparison of the two approaches (AQUA and IHC) for the same four markers demonstrated AQUA analyses of tumors represented in TMAs provide reliable, quantitative measures of marker expression. Recently, we built a new set of TMAs (TMA2) including 919 Polish breast cancer cases with three-fold redundancy. Combined, TMA1 and TMA2, have 1,500 invasive tumors with at least two-fold redundancy. We have stained the new arrays (TMA2) for all five molecular signature markers and the old arrays (TMA1) for CK5 and EGFR using AQUA, which gave us AQUA data for all five signature markers from a complete set of invasive breast cancer cases built on TMAs. We have also established a technique in constructing TMAs from non-invasive epithelial tissues (normal terminal duct lobular units [TDLUs] and ductal carcinoma in situ [DCIS]), and successfully built 32 TMA blocks of 1,547 tissue cores including both non-invasive (normal TDLUs [N=689] and DCIS [N=501]) tissues and their associated invasive tumors (N=357) collected from 560 Polish breast cancer cases. We have stained these non-invasive arrays with all five molecular signature markers and analysis is in process. Renal cell carcinoma (RCC) rates in Central and Eastern Europe are among the highest in the world. The von Hippel Lindau-Hypoxia Inducible Factor (VHL-HIF) pathway has been implicated in kidney cancer tumorigenesis. We investigated the role of common variants in genes in the VHLHIF pathway in the susceptibility of sporadic RCC and clear cell RCC. We identified common genetic variants in genes in the VHL-HIF pathway associated with kidney cancer risk. We plan to replicate the finding in additional study populations. Analyses of registry data from Sweden and Denmark are continuing. We conducted analyses of medical conditions associated with CLL and multiple myeloma (MM) and showed an increased risk for respiratory infections and both CLL and MM, suggesting that they may trigger a malignant process in susceptible individuals. We also demonstrated that family history of cancer increased risk of individuals with lymphoma to develop certain second cancers. We are conducting a new study using laboratory and population registry data from Sweden to quantify personal and familial associations of monoclonal gammopathy of uncertain significance (MGUS) with other LP tumors. Approximately 4500 MGUS cases were identified from all of the major hematologyoncology units in Sweden who had linkable relatives. Compared with controls, relative risk (RR) of MGUS was significantly increased in relatives of MGUS cases. Risks of MM, WM, and CLL were also increased. Risk-estimates were similar for parents, siblings, and offspring; the same was true when we estimated risks by age at MGUS of cases (above vs. below 65 yrs), and sex of relatives. There was no increased risk of NHL or HL among relatives of MGUS cases. Preliminary analyses of relatives of WM cases showed that they had a higher risk of MGUS, WM, and CLL but not MM. This supports our data from high risk families indicating a genetic association between certain MGUS subtypes, WM, and CLL. We have also begun to analyze myeloproliferative (MPD) malignancies including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) using similar methodology. Preliminary results indicate that the relative risks for developing any MPD in first degree relatives of MPD patients are highly elevated (RR=5.6, 95% CI, 3.8-8.2).

该遗传流行病学项目中的许多研究源于对癌症高风险或其他病因学研究的家庭观察。调查表数据，肿瘤和DNA来自一项病例对照研究，对意大利东北部进行的183例黑色素瘤病例和179例对照进行了评估，以评估黑色素皮质素-1受体（MC1R）基因（MC1R）基因，该基因是人类色素沉着的主要调节剂，在人类中的braf Oncogene sompations in Cycogene symanty cymanse transans transass transans in trands transans in trands transass in trands trands trands trands introve transs inthe trands trands trands in trandy introve trands introve。 在黑色素瘤的受试者在人体暴露区域且慢性太阳损害有限的受试者中，我们发现MC1R种系变体与黑色素瘤与BRAF癌基因中的体细胞突变之间存在很强的关联。我们计划首先验证这种关联以及潜在修饰符在独立人群中的作用。在20-40％的高风险黑色素瘤家族中已经观察到种系CDKN2A突变，但是对于基于人群的病例和对照中的患病率却一无所知。多种MC1R变体与黑色素瘤风险增加有关。冰岛人群的红头发和金发颜色受试者的频率很高，使其成为评估MC1R差异的理想人群。我们在703个注册表中的CDKN2A和MC1R基因重新计算了冰岛，冰岛的基于冰岛的691例基于人群的控制，这是黑色素瘤的发病率增加的国家。缔合的评估正在进行中。导致黑色素瘤发展的潜在途径之一包括丧失了常见黑素细胞NEVI的调节，这些nevi获得了可取得异型或发育不良的特征，这些特征可以进一步进化，从而进一步发展。为了研究这一途径，我们目前正在收集来自意大利东北部相同受试者的黑色素瘤的正常皮肤，常见的黑色素核NEVI，发育不良的NEVI，黑色素瘤和转移。当样本量达到100名受试者时，我们计划研究细胞周期，端粒和连续组织样品中的多个基因中突变的表达和存在，以探索通过nevi的大脑/病例研究的综合病例研究中的365例GLIOMA案例的黑素瘤发展的机制。与人口对照相比，已经完成了一级亲属中癌症风险的分析。对儿童髓母细胞瘤的回顾性单一机构研究的问卷数据检查显示，几乎没有证据表明髓母细胞瘤患者亲属增加了癌症风险。结是一种罕见的原发性恶性骨肿瘤，主要是在轴向骨骼中引起的，该骨骼骨骼中的其余部分因胚胎诺达尔干细胞的其余部分失败而导致正常的正常调节失败。 我们与波士顿马萨诸塞州总医院的放射肿瘤学系启动了合作，试图识别核心瘤家庭，以帮助映射和识别脊柱易感基因。该项目涉及从最有可能患有遗传易感性的患者亚组的个人病史，颊细胞和肿瘤组织的幻灯片：脊全瘤<18岁的患者。在过去的一年中，我们完成了45例脊索瘤患者的入学人数。 我们正在从中获得个人和家庭病史，颊细胞和肿瘤组织。与耶鲁大学组织微阵列（TMA）核心设施合作，我们成功地建立了从波兰乳腺癌研究中收集的842个浸润性肿瘤（TMA1）的TMA。我们对与激素生物合成，代谢和受体介导的途径有关的18个分子标记物进行了免疫组织化学染色。对这些标志物的分析表明，乳腺癌的危险因素可能因分子亚型和以激素标记的共表达为特征的激素途径而异。我们还使用新开发的自动定量分析（Aqua）对四个标记（ER-Alpha，Er-Beta，PR和HER2）染色了这些阵列。对相同四个标记的两种方法（Aqua和IHC）的比较表明，对TMA中代表的肿瘤进行了aqua分析，提供了可靠的定量标记表达度量。最近，我们建立了一组新的TMA（TMA2），其中包括919例冗余三倍的波兰乳腺癌病例。 TMA1和TMA2的结合具有1,500个浸润性肿瘤，至少具有两倍的冗余性。我们使用Aqua染色了所有五个分子签名标记物的新阵列（TMA2），并使用Aqua染色了CK5和EGFR的旧阵列（TMA1），这为我们提供了所有五个签名标记的Aqua数据，该标记是由一组完整的侵入性乳腺癌病例构建在TMA上的完整侵入性乳腺癌病例。我们还建立了一种技术，可以从非侵入性上皮组织（正常的终末导管叶[TDLUS]和导管癌[DCIS]）中构建TMA，并成功构建了32个TMA块，其中32个TMA块，包括1,547个核心，包括非侵入性的（正常TDLUS [n = 689]），包括非侵入性的n = 689] [N = 689] [n = 689] [n = 689]从560例波兰乳腺癌病例收集的浸润性肿瘤（n = 357）。我们已经用所有五个分子签名标记染色了这些非侵入性阵列，并且正在进行分析。中欧和东欧的肾细胞癌（RCC）率是世界上最高的。 von Hippel lindau催眠因子（VHL-HIF）途径已与肾癌肿瘤发生有关。 我们研究了普通变体在基因在VHLHIF途径中的作用在零星RCC和透明细胞RCC敏感性中的作用。我们确定了与肾癌风险相关的VHL-HIF途径中基因中的常见遗传变异。 我们计划在其他研究人群中复制这一发现。来自瑞典和丹麦的注册表数据的分析仍在继续。 我们对与CLL和多发性骨髓瘤（MM）相关的医疗状况进行了分析，并显示出呼吸道感染以及CLL和MM的风险增加，这表明它们可能会引发易感人群的恶性过程。我们还证明，癌症的家族史增加了淋巴瘤患者发展某些第二癌的风险。我们正在使用瑞典的实验室和人口注册表数据进行一项新研究，以量化与其他LP肿瘤具有不确定意义（MGU）的单克隆性伽马病的个人和家族关联。从瑞典的所有主要血液学单元中鉴定出约4500例MGU病例。与对照组相比，MGUS病例的亲属中MGU的相对风险（RR）显着增加。 MM，WM和CLL的风险也增加了。父母，兄弟姐妹和后代的风险估计相似。当我们按年龄估算案件的年龄（以上比65岁以下）和亲戚的性别估计风险时，情况也是如此。在MGU案件的亲属中，NHL或HL的风险没有增加。对WM病例的亲属的初步分析表明，它们的MGU，WM和CLL风险更高，但不是MM。这支持了我们来自高风险家族的数据，表明某些MGUS亚型，WM和CLL之间存在遗传关联。我们还开始使用类似的方法来分析包括多性细胞增多症（PV），必需血小板血症（ET）和骨髓纤维纤维化（MF）在内的脊髓增生性（MPD）恶性肿瘤（MF）。初步结果表明，在MPD患者一级亲戚中开发任何MPD的相对风险高度升高（RR = 5.6，95％CI，3.8-8.2）。