GENOMIC ANALYSIS OF INHERITED BREAST AND OVARIAN CANCER

 描述(申请人提供)：在美国，每年有230,000名妇女被诊断出患有乳腺癌，40,000名妇女死于此病；21,000名妇女被诊断出患有卵巢癌，14,000名妇女死于卵巢癌；家族史是这些癌症中每一种癌症最重要的风险因素之一，但大多数风险仍未得到解释。在我的整个科学生涯中，我一直在努力解决这个问题。BRCA1和BRCA2的发现、它们的特征以及将这些发现转化为临床实践无疑产生了不同。这项提议是我的计划，目的是在那些仍未解决的家族中确定遗传性乳腺癌的遗传原因。我的假设是，乳腺癌和卵巢癌的剩余遗传易感性是由于许多不同的、个别罕见的严重影响的突变。我认为其中一些突变存在于已知乳腺癌和卵巢癌基因的遥远调节区：编码序列和邻近区域在我们的研究中已经得到了彻底的筛选。我进一步认为，其他突变可能会改变尚不为人所知的与这些癌症遗传易感性相关的基因。我建议识别这些突变、包含它们的基因以及它们的作用机制。我的方法将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。我建议从三个方面同时解决这个问题： *在所有已知乳腺癌和卵巢癌基因序列正常的严重受乳腺癌或卵巢癌影响的大家族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正常序列的德系犹太血统年轻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 *在卵巢癌、输卵管癌和腹膜癌标本中发现新的候选基因，这些基因具有BRCA1、BRCA2的体细胞突变特征，可能还有其他参与同源重组的基因，这些患者已经对已知卵巢癌基因的种系突变进行了评估 除了我，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，使所有与遗传性乳腺癌和卵巢癌有关的突变基因能够整合到临床实践中。

 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