EPIDEMIOLOGIC AND GENETIC STUDIES OF BREAST CANCER

项目描述（申请人描述）拟提交一份关于乳腺癌遗传流行病学的P01。它建立在426个四到五代家庭的独特资源的基础上，这些家庭是通过1940年至1952年间最初确定的乳腺癌患者确定的。在R01资助的5年中，重要的观测丰富了这一资源。本项目的主题是基因和环境在该疾病发病机制中的相互作用。这些多代家庭为研究这一重要课题提供了明显的优势。项目1旨在I)确定260个至少有2例乳腺癌或卵巢癌的家庭群体样本中BRCA1和BRCA2基因改变的频率，II)探索基因与环境风险的相互作用。项目2旨在验证在多态性基因控制下的雌激素生物激活可能导致DNA的直接遗传毒性和乳腺癌风险增加的假设。项目3是一项遗传联系研究，旨在确定与乳腺密度增加相关的基因的染色体位置，乳腺密度增加是乳腺癌的主要危险因素。项目4是对这群强大的家庭的后续研究。它旨在调查乳腺密度的自然史，并将研究青少年饮食和早期生活暴露的重要新风险因素数据。此外，这项后续调查将为项目1和项目2确定更多的乳腺癌病例。这些项目得到了四个核心的支持，这四个核心对实施整个P01至关重要：管理、生物统计学、乳房x光检查和流行病学。调查小组是多学科的，经验丰富，并具有富有成效的合作历史。这个重要项目的发现可能对我们了解乳腺癌的遗传流行病学至关重要。

DESCRIPTION (Applicants Description) A P01 on the genetic epidemiology of breast cancer is proposed. It builds upon a unique resource of 426 four-to five-generation families ascertained through breast cancer patients originally ascertained between 1940 and 1952. Important observations have enriched this resource during 5 years of funding from an R01. The theme of this project is the interaction of genes and environment in the pathogenesis of this disease. These multi generation families offer distinct advantages in efforts to investigate this important subject. Project 1 seeks to I) determine the frequency of genetic alterations in BRCA1 and BRCA2 in a population-based sample of 260 families with at least two cases of breast or ovarian cancer and, II) to explore geno-environment risk interactions. Project 2 is designed to test the hypothesis that Bioactivation of estrogens, under the control of polymorphic genes, can lead to direct genotoxicity of DNA and increased risk of breast cancer. Project 3 is a genetic linkage study to identify the chromosomal location of a gene that is associated with increased mammographic breast density, a major risk factor for breast cancer. Project 4 is a follow up study of this powerful cohort of families. It seeks to investigate the natural history of mammographic breast density, and will examine important new risk factor data on adolescent diet and early life exposures. In addition, this follow-up survey will ascertain additional breast cancer cases for Projects 1 and 2. The projects are supported by four cores that are essential to carry out the overall P01: administration, biostatistics, mammography, and epidemiology. The investigative team is multidisciplinary, experienced, and brings a history of productive collaborations. The findings from this important project could be critical to our understanding of the genetic epidemiology of breast cancer.