Genetic Epidemiology

这个遗传流行病学项目中的许多调查都来自于对癌症高危家庭或其他病因学研究的观察。采用病例对照研究资料，对718例来自费城和旧金山黑色素瘤诊所的非西班牙裔白人侵袭性皮肤黑色素瘤患者和945例来自与病例集水区相似的门诊对照进行了研究，以建立一个估计黑色素瘤5年绝对风险的风险评估模型。风险评估工具可在http://www.cancer.gov/melanomarisktool/的网站上获得。使用性别特定的模型，使用卫生保健专业人员容易获得的简单变量，男性患黑色素瘤的归因风险为86%，女性为89%。问卷数据、肿瘤块和来自意大利东北部进行的183例黑色素瘤病例和179名对照的病例对照研究的DNA被用来进一步评估MC1R和BRAF。在发生在身体暴露在阳光下的黑色素瘤和慢性日光损伤的有限迹象的受试者中，我们发现MC1R胚系变异和黑色素瘤与BRAF癌基因的体细胞突变有很强的相关性。我们现在正在分析其他参与黑色素生成和信号转导途径的基因，以进一步探索黑色素瘤的病因。作为DCEG对成年脑瘤患者进行的全面病例对照研究的后续行动，我们对480例符合条件的胶质瘤病例的父母、兄弟姐妹和成年子女进行了一项基于家庭的研究。365名胶质瘤患者的亲属接受了关于个人和家庭病史和其他风险因素的采访，并被要求提供口腔细胞作为DNA的来源。与人口控制相比，对一级亲属患癌症风险的分析正在进行中。对儿童髓母细胞瘤的一项单一机构回顾性研究的问卷数据的检查显示，几乎没有证据表明髓母细胞瘤患者亲属的癌症风险增加。与耶鲁大学组织芯片(TMA)核心设施合作，我们成功地建立了842个侵袭性肿瘤的TMA，这些肿瘤具有双重冗余，收集自波兰进行的一项基于人群的乳腺癌病例对照研究。我们用免疫组织化学方法对这些TMA进行了18个分子标记的染色，这些标记涉及激素的生物合成、代谢和受体介导的途径。对分子标志物(ER-α、PR、HER2、EGFR和细胞角蛋白5)的分析表明，乳腺癌的危险因素可能因分子亚型而异。我们还使用新开发的自动定量分析(Aqua)对这些阵列进行了四种标记(ER-α、ER-β、PR和HER2)的染色。对同一四种标记物的两种方法(AQUA和IHC)的比较表明，对TMA中出现的肿瘤进行AQUA分析可以提供可靠的、定量的标记物表达测量。目前，耶鲁大学正在建造一套新的侵袭性TMA，其中包括919例具有三重冗余的波兰乳腺癌病例。一旦完成，我们将有1761个侵袭性肿瘤，至少有两倍的冗余建立在TMA上。我们已经发表了详细的结果，详细描述了一种从非侵入性上皮组织构建TMA的技术挑战方法。使用这项技术，我们已经成功地建立了32个TMA块，包括来自560例波兰乳腺癌病例的1547个组织核心，包括非侵袭性组织及其相关的侵袭性肿瘤(N=357)。我们用ER-α、PR和HER2对这些非侵入性阵列进行了染色。我们将利用这些TMA作为平台来研究乳腺癌的病因学异质性，其特征是分子标志物在浸润性肿瘤及其邻近的非侵袭性上皮病变和间质组织中的表达模式。

Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. Case-control study data from 718 non-Hispanic white patients with invasive cutaneous melanoma from melanoma clinics in Philadelphia and San Francisco and 945 matched controls from outpatient clinics with similar catchment areas to the cases were used to develop a risk assessment model for estimating 5 year absolute risk of melanoma. The risk assessment tool is available on the web at http://www.cancer.gov/melanomarisktool/ . The attributable risks of melanoma using the gender specific models were 86% for men and 89% for women using simple variables that are easily obtainable by health care professionals. Questionnaire data, tumor blocks, and DNA from a case-control study of 183 incident melanoma cases and 179 controls conducted in North-Eastern Italy were used to further evaluate MC1R and BRAF. In subjects with melanoma arising on sun exposed areas of the body and with limited signs of chronic solar damage, we found a strong association between MC1R germline variants and melanoma with somatic mutations in the BRAF oncogene. We are now analyzing other genes involved in melanogenesis and signal transduction pathways to further explore the etiology of melanoma.As a follow-up to a DCEG comprehensive case-control study of adults with brain tumors, a family-based study of the parents, siblings and adult children of the 480 eligible glioma cases has been conducted. Relatives of 365 of the glioma cases were interviewed about personal and family medical history and other risk factors and were asked to provide buccal cells as a source of DNA. Analyses to examine the risk of cancer among the first degree relatives compared to population controls are in process. 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.In collaboration with Yale University Tissue Microarray (TMA) core facility, we have successfully built TMAs of 842 invasive tumors, with two-fold redundancy, collected from a population-based case-control study of breast cancer conducted in Poland. We have immunohistochemically stained these TMAs for 18 molecular markers involved in hormone biosynthesis, metabolism, and receptor mediated pathways. Analyses of molecular signature markers (ER-alpha, PR, HER2, EGFR, and cytokeratin 5) suggest that risk factors for breast cancer may vary by molecular subtypes. 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. Currently, a new set of invasive TMAs including 919 Polish breast cancer cases with three-fold redundancy is being constructed at Yale. Once completed, we will have 1,761 invasive tumors with at least two-fold redundancy built on TMAs. We have published results detailing a technically challenging method to construct TMAs from non-invasive epithelial tissues. Using this technique, we have successfully built 32 TMA blocks of 1,547 tissue cores including both non-invasive tissues and their associated invasive tumors (N=357) collected from 560 Polish breast cancer cases. We have stained these non-invasive arrays with ER-alpha, PR, and HER2. We will use these TMAs as platforms to study etiologic heterogeneity of breast cancer characterized by expression patterns of molecular markers in both invasive tumors and their adjacent non-invasive epithelial lesions and stromal tissues.