EPIDEMIOLOGIC AND GENETIC STUDIES OF BREAST CANCER

描述(申请人描述)提出了一项关于乳腺癌遗传流行病学的P01。它建立在由426个四至五代家庭组成的独特资源的基础上，这些家庭最初是在1940年至1952年间通过乳腺癌患者确定的。重要的观察结果在R01资助的5年中丰富了这一资源。这个项目的主题是在这种疾病的发病机制中基因和环境的相互作用。这些多代家庭在努力研究这一重要课题方面提供了明显的优势。项目1旨在：i)在260个至少有两例乳腺癌或卵巢癌病例的家庭的人群样本中，确定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旨在检验这样一种假设，即在多态基因的控制下，雌激素的生物激活可以导致DNA的直接遗传毒性和乳腺癌风险的增加。项目3是一项基因连锁研究，旨在确定与乳房X光检查乳房密度增加相关的基因的染色体位置，乳房密度增加是乳腺癌的主要风险因素。项目4是对这一强大的家庭队列的后续研究。它试图调查乳房X光检查乳房密度的自然历史，并将检查有关青少年饮食和早期生活暴露的重要新风险因素数据。此外，这项后续调查将确定项目1和项目2的额外乳腺癌病例。这些项目得到四个核心的支持，这四个核心是执行总体P01所必需的：行政、生物统计学、乳房X光摄影和流行病学。调查团队是多学科的，经验丰富，并带来了富有成效的合作历史。这一重要项目的发现可能对我们理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.