IDENTIFYING MODIFYING GENES IN BRCA1 MUTATION CARRIERS

BRCA1的胚系突变使女性携带者患乳腺癌和卵巢癌的风险很高。然而，乳腺癌的发病年龄可能有很大的差异，即使是在同一个家庭中的不同个体之间也是如此。目前，有几条证据表明，BRCA1突变导致的乳腺癌和卵巢癌风险可能与其他基因有关。BRCA1突变携带者的乳腺癌发病年龄和估计的乳腺癌终生风险的变异性取决于确定的人群，这是第一批提示性证据。其次，越来越多的证据表明，BRCA1和BRCA2突变并不能完全解释家族性乳腺癌的风险。最后，来自几个关联研究的初步数据，关注HRAS、APC、雄激素受体、AIB1、hRad51和Nat2，表明这些基因的某些等位基因改变了BRCA1突变携带者的外显性。所有这些不同的证据都清楚地表明，我们假设，除了突变状态之外，其他遗传因素也会影响BRCA1和BRCA2突变携带者的癌症风险。这项建议旨在确定BRCA1突变携带者中影响乳腺癌外显性的基因。我们目前有来自109个BRCA1突变家庭的样本；这个样本集将在研究的第一部分扩大。我们将使用两种方法来研究BRCA1外显性的修饰基因：第一，我们将从DNA修复途径中检查候选基因与乳腺癌表型的任何关联；第二，我们将进行全基因组搜索，寻找可能包含新基因的基因组区域。该提案概述了一项为期五年的培训计划，该计划将允许应聘者掌握独立内科科学家所需的技能和经验。该教育计划将结合遗传流行病学的培训和动手实验室的经验，提供广泛的知识基础。这项研究提案将使候选人能够转变为一名独立的调查者，能够在未来的癌症遗传学分子基础研究中整合突变分析、基因分型、统计遗传学和临床诊断。

Germline mutations in BRCA1 confer a high risk of breast and ovarian cancers to female carriers. However, the age of onset of breast cancer can vary substantially, even between individuals in the same family. Currently several lines of evidence suggest that other genes modify the breast and ovarian cancer risk conferred by BRCA1 mutations. The variability in age of onset of breast cancer and estimated lifetime risk of breast cancer for BRCA1 mutation carriers depending on the population of ascertainment were the first pieces of suggestive evidence. Secondly, there is accumulating evidence that familial breast cancer risk is not entirely accounted for by mutations in BRCA1 and BRCA2. Finally, there is preliminary data from several association studies, looking at HRAS, APC, the androgen receptor, AIB1, hRad51 and NAT2, which demonstrate that certain alleles of these genes modify penetrance in BRCA1 mutation carriers. All of these various lines of evidence clearly suggest, and we hypothesize, that other genetic factors in addition to mutation status influence cancer risk in BRCA1 and BRCA2 mutation carriers. This proposal seeks to identify genes which modify breast cancer penetrance in BRCA1 mutation carriers. We currently have samples from 109 families with BRCA1 mutations; this sample set will be enlarged in the first part of the study. Two approaches will be utilized to study modifiers of BRCA1 penetrance; first we will examine candidate genes from DNA repair pathways for any association with breast cancer phenotype and secondly we will conduct a genome wide search to look for genomic regions that may contain novel genes. This proposal outlines a five year training program which will allow the candidate to the skills and experience required of an independent physician-scientist. The educational program will combine training in genetic epidemiology and hands-on laboratory experience to provide a broad knowledge base. The research proposal will enable the candidate to transition into an independent investigator capable of integrating mutation analysis, genotyping, statistical genetics and clinical diagnosis in future studies of the molecular basis of the genetics of cancer.