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研究源于对癌症高风险或其他病因学研究的家庭观察。病例对照研究的数据数据来自费城和旧金山黑色素诊所的718例非西班牙裔白人皮肤黑色素瘤，以及945个与该病例相似的门诊诊所的对照组相匹配，用于开发估计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/上找到。使用特定于性别模型的黑色素瘤的归因风险为男性86％，女性使用简单变量的女性为89％，这些变量很容易由医疗保健专业人员获得。调查表数据，肿瘤块和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例对照进行了进一步评估MC1R和BRAF。在黑色素瘤的受试者在人体暴露区域出现的受试者中，慢性太阳能损害的迹象有限，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。现在，我们正在分析与黑色素生成和信号转导途径有关的其他基因，以进一步探索黑色素瘤的病因。作为DCEG全面的脑肿瘤成年人的全面病例对照研究的随访，这是对父母，兄弟姐妹和成人儿童的基于家庭合格Gliomoma病例的家庭研究。对365例神经胶质瘤病例的亲戚进行了有关个人和家族病史和其他危险因素的采访，并被要求提供颊细胞作为DNA的来源。与人口对照相比，一级亲属中癌症风险的分析正在进行中。对儿童髓母细胞瘤的回顾性单一机构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的亲属之间的癌症风险增加了。在与耶鲁大学组织组织微阵列（TMA）核心设施的合作中，我们成功地建立了842个TMA，构建了842个Invasive肿瘤，并从乳腺癌中进行了两轮型癌症，对乳腺癌进行了癌症，该癌症是对人群造成的。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。分子签名标记物（ER-Alpha，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。目前，在耶鲁大学正在建造一套新的入侵性TMA，其中包括919个波兰乳腺癌病例，其中有三倍的冗余。完成后，我们将有1,761种侵入性肿瘤，其中至少在TMA上构建了两倍的冗余。我们发表了结果，详细介绍了一种技术挑战性的方法，可以从非侵入性上皮组织中构建TMA。使用这种技术，我们成功地建立了32个TMA块，其中包括1,547个组织核心，包括非侵入性组织及其相关的浸润性肿瘤（n = 357），这些肿瘤（n = 357）从560个波兰乳腺癌病例中收集。我们用ER-Alpha，PR和HER2染色了这些无创阵列。我们将使用这些TMA作为平台来研究乳腺癌的病因异质性，其特征在于浸润性肿瘤及其相邻的非侵入性上皮病变和基质组织中分子标记的表达模式。