IDENTIFYING MODIFYING GENES IN BRCA1 MUTATION CARRIERS

BRCA 1的生殖系突变赋予女性携带者患乳腺癌和卵巢癌的高风险。 然而，乳腺癌的发病年龄可能有很大差异，甚至在同一家庭的个体之间。 目前有几条证据表明，其他基因改变了BRCA 1突变所带来的乳腺癌和卵巢癌风险。 乳腺癌发病年龄的变化和BRCA 1突变携带者乳腺癌的估计终生风险取决于确定的人群是第一个提示性证据。其次，越来越多的证据表明，家族性乳腺癌风险并不完全是由BRCA 1和BRCA 2突变引起的。 最后，从几项关联研究中获得的初步数据，包括HRAS、APC、雄激素受体、AIB 1、hRad 51和NAT 2，表明这些基因的某些等位基因改变BRCA 1突变携带者的遗传易感性。 所有这些不同的证据清楚地表明，我们假设，除了突变状态之外，其他遗传因素也会影响BRCA 1和BRCA 2突变携带者的癌症风险。这项提议旨在确定BRCA 1突变携带者中改变乳腺癌转移率的基因。 我们目前有来自109个BRCA 1突变家庭的样本;这个样本集将在研究的第一部分扩大。 两种方法将用于研究BRCA 1突变的修饰剂;首先，我们将检查来自DNA修复途径的候选基因与乳腺癌表型的任何关联，其次，我们将进行全基因组搜索，以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，该计划将使候选人获得独立医生-科学家所需的技能和经验。 教育计划将结合联合收割机培训遗传流行病学和动手实验室的经验，提供一个广泛的知识基础。 该研究计划将使候选人能够转变为能够在未来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的独立研究者。

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.