IDENTIFYING MODIFYING GENES IN BRCA1 MUTATION CARRIERS

BRCA1的种系突变使女性携带者罹患乳腺癌和卵巢癌的风险很高。然而，即使是同一家庭的个体，乳腺癌的发病年龄也可能有很大差异。目前有几条线索表明，其他基因可以改变BRCA1突变带来的乳腺癌和卵巢癌风险。乳腺癌发病年龄的变异性和BRCA1突变携带者一生中乳腺癌的估计风险取决于确定的人群，这是第一个暗示性证据。其次，越来越多的证据表明，家族性乳腺癌的风险并不完全由BRCA1和BRCA2突变决定。最后，通过对HRAS、APC、雄激素受体、AIB1、hRad51和NAT2的关联研究，得出了一些初步数据，这些数据表明，这些基因的某些等位基因可以改变BRCA1突变携带者的外显率。所有这些不同的证据都清楚地表明，我们假设，除了突变状态外，其他遗传因素也会影响BRCA1和BRCA2突变携带者的癌症风险。本研究旨在确定改变BRCA1突变携带者乳腺癌外显率的基因。我们目前有来自109个BRCA1突变家族的样本；这个样本集将在研究的第一部分扩大。我们将采用两种方法研究BRCA1外显率的修饰因子；首先，我们将检查与乳腺癌表型相关的DNA修复途径中的候选基因，其次，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。该提案概述了一个为期五年的培训计划，该计划将使候选人具备独立医师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培训和动手实验室经验，以提供广泛的知识基础。该研究计划将使候选人能够转变为一名独立的研究者，能够在癌症遗传学分子基础的未来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.