Genetic Epidemiology

遗传流行病学

• 批准号: 7330722
• 负责人: ALISA GOLDSTEIN
• 金额: --
• 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/7330722
• 关键词: Genetic; Epidemiology

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.

该遗传流行病学项目中的许多调查源于对癌症高风险家庭的观察或其他病因学研究。病例对照研究数据来自费城和旧金山黑色素瘤诊所的 718 名患有侵袭性皮肤黑色素瘤的非西班牙裔白人患者，以及来自与病例类似的服务区的门诊诊所的 945 名匹配对照数据，用于开发风险评估模型，用于估计 5 年黑色素瘤的绝对风险。该风险评估工具可在以下网址获取：http://www.cancer.gov/melanomarisktool/。使用医疗保健专业人员可以轻松获得的简单变量，使用特定性别模型得出的黑色素瘤归因风险，男性为 86%，女性为 89%。使用在意大利东北部进行的 183 例黑色素瘤病例和 179 例对照病例对照研究中的问卷数据、肿瘤块和 DNA 来进一步评估 MC1R 和 BRAF。在身体暴露于阳光的部位出现黑色素瘤且慢性日光损伤迹象有限的受试者中，我们发现 MC1R 种系变异与 BRAF 癌基因体细胞突变的黑色素瘤之间存在很强的关联。我们现在正在分析参与黑色素生成和信号转导途径的其他基因，以进一步探讨黑色素瘤的病因。 作为 DCEG 成人脑肿瘤综合病例对照研究的后续行动，我们对 480 名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 名神经胶质瘤病例的亲属接受了采访，了解个人和家族病史以及其他危险因素，并被要求提供口腔细胞作为 DNA 来源。与人群对照相比，对一级亲属患癌症风险的分析正在进行中。对儿童髓母细胞瘤回顾性单一机构研究的问卷数据进行检查后发现，几乎没有证据表明髓母细胞瘤患者亲属的癌症风险增加。与耶鲁大学组织微阵列 (TMA) 核心设施合作，我们成功构建了 842 个侵袭性肿瘤的 TMA，具有两倍冗余，这些肿瘤是从波兰进行的一项基于人群的乳腺癌病例对照研究中收集的。我们对这些 TMA 进行了免疫组织化学染色，检测涉及激素生物合成、代谢和受体介导途径的 18 种分子标记。分子特征标志物（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物（ER-α、ER-β、PR 和 HER2）的染色。对相同四种标志物的两种方法（AQUA 和 IHC）进行比较表明，对 TMA 中代表的肿瘤进行 AQUA 分析可以提供可靠的标志物表达定量测量。目前，耶鲁大学正在构建一套新的侵入性 TMA，其中包括 919 例波兰乳腺癌病例，冗余度达到三倍。一旦完成，我们将拥有 1,761 个基于 TMA 的具有至少两倍冗余的侵袭性肿瘤。我们已经发表了结果，详细介绍了从非侵入性上皮组织构建 TMA 的技术上具有挑战性的方法。利用这项技术，我们成功构建了 1,547 个组织核心的 32 个 TMA 块，包括从 560 个波兰乳腺癌病例中收集的非侵袭性组织及其相关的侵袭性肿瘤 (N=357)。我们用 ER-alpha、PR 和 HER2 对这些非侵入性阵列进行了染色。我们将使用这些 TMA 作为平台来研究乳腺癌的病因异质性，其特征是侵袭性肿瘤及其邻近的非侵袭性上皮病变和间质组织中分子标记的表达模式。