GENOMIC ANALYSIS OF INHERITED BREAST AND OVARIAN CANCER

 描述（由申请人提供）：每年在美国，230，000名妇女被诊断患有乳腺癌，40，000名妇女死于乳腺癌; 21，000名妇女被诊断患有卵巢癌，14，000名妇女死于卵巢癌;家族史是每种癌症最重要的风险因素之一，但大多数风险仍然无法解释。我的整个科学生涯都在与这个问题作斗争。BRCA 1和BRCA 2的发现、它们的特征以及这些发现在临床实践中的应用无疑产生了影响。这个建议是我的计划，以确定遗传性乳腺癌的遗传原因，在这些家庭仍然没有解决。我的假设是，乳腺癌和卵巢癌的遗传易感性是由于许多不同的，个别罕见的突变严重的影响。我认为这些突变中的一些位于已知乳腺癌和卵巢癌基因的远端调控区：编码序列和近端区域已经在我们的研究中彻底筛选过。我进一步认为，其他突变可能会改变基因，这些基因目前还不知道与这些癌症的遗传易感性有关。我建议确定这些突变，携带它们的基因，以及它们的作用机制。我的方法是将全基因组测序与生物信息学工具的应用和开发以及实验生物学相结合。我建议从三个方向同时处理这个问题： * 在所有已知乳腺癌和卵巢癌基因序列正常的乳腺癌或卵巢癌严重影响的扩展激酶中发现新的突变机制和新基因 * 在具有所有已知乳腺癌和卵巢癌基因的正常序列的德系犹太人血统的新发乳腺癌患者中发现创始人突变，然后比较独立AJ病例和AJ人群对照中潜在关键创始人等位基因的频率 * 在来自已评估已知卵巢癌基因生殖系突变的患者的卵巢癌、输卵管癌和腹膜癌标本中，通过BRCA 1、BRCA 2和可能参与同源重组的其他基因的体细胞突变特征揭示的新候选基因的发现 除了我之外，从事这项工作的研究人员还有年轻的遗传学家、生物信息学家、分子生物学家和外科肿瘤学家。我们在全基因组测序方面的合作伙伴是贝勒医学院人类基因组测序中心。我们的共同目标是提供必要的信息，使所有基因突变负责遗传性乳腺癌和卵巢癌被纳入临床实践

 DESCRIPTION (provided by applicant): Each year in the U.S., 230,000 women are diagnosed with breast cancer and 40,000 women die of it; 21,000 women are diagnosed with ovarian cancer and 14,000 women die of it; family history is one of the most important risk factors for each of these cancers, yet most of that risk remains unexplained. I have been wrestling with this problem my entire scientific life. The discoveries of BRCA1 and BRCA2, their characterization, and the translation of these discoveries to clinical practice have unquestionably made a difference. This proposal is my plan to identify the genetic causes of inherited breast cancer in those families that remain unsolved. My hypothesis is that the remaining genetic predisposition to breast and ovarian cancer is due to many different, individually rare mutations of severe effect. I suggest that some of these mutations lie in distant regulatory regions of known breast and ovarian cancer genes: the coding sequences and the close-in regions having already been thoroughly screened in our studies. I further suggest that other mutations likely alter genes not yet known to be involved in inherited predisposition to these cancers. I propose to identify these mutations, the genes that harbor them, and the mechanisms by which they act. My approach will be to integrate whole genome sequencing with application and development of bioinformatics tools and with experimental biology. I propose to address the problem from three directions simultaneously: * Discovery of new mutational mechanisms and new genes in extended kindreds severely affected by breast or ovarian cancer with normal sequences of all known breast and ovarian cancer genes * Discovery of founder mutations in young-onset breast cancer patients of Ashkenazi Jewish ancestry who have normal sequences of all known breast and ovarian cancer genes, then comparing the frequencies of potentially critical founder alleles in independent AJ cases and AJ population controls * Discovery of new candidate genes revealed by somatic mutation signatures characteristic of BRCA1, BRCA2, and perhaps other genes involved in homologous recombination, in ovarian, fallopian tube, and peritoneal cancer specimens from patients already evaluated for germline mutations in known ovarian cancer genes In addition to me, the investigators undertaking this effort are young geneticists, bioinformaticists, molecular biologists, and surgical oncologists. Our partners in whole genome sequencing are the Baylor College of Medicine Human Genome Sequencing Center. Our shared goal is to provide the information necessary to enable all genes with mutations responsible for inherited breast and ovarian cancer to be integrated into clinical practice