Identification of new hereditary ovarian cancer genes through investigation of exceptional responders to platinum-based therapy

通过调查铂类治疗的特殊反应者来鉴定新的遗传性卵巢癌基因

• 批准号: 429812149
• 负责人: Dr. Thilo Dörk-Bousset
• 金额: --
• 依托单位: N.N. Petrov National Medicine Research Center of Oncology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/429812149?language=en
• 关键词: Identification; new; hereditary; ovarian; cancer

A significant proportion of ovarian cancer incidence is attributed to the inherited germ-line mutations. Approximately 15% of ovarian cancer patients carry germ-line mutations in BRCA1 and BRCA2, and there are additional hereditary variants in recently identified ovarian cancer susceptibility genes, with the most comprehensive data obtained for BRIP1, RAD51C and RAD51D. Yet a large proportion of familial ovarian cancer clustering remains unexplained by known germ-line mutations. Given the failure of family-based studies to identify additional ovarian cancer susceptibility genes, there is a need for alternative approaches for discovery of new hereditary ovarian cancer genes. Because the hitherto known gene mutations impact on DNA crosslink and homologous recombinational repair, we hypothesize that the exome analysis of mutation-negative exceptional responders to platinum therapy will greatly help to identify previously unappreciated genes for hereditary ovarian cancer.In this project we aim to identify hereditary mutations in new ovarian cancer genes through whole exome sequencing analysis of 100 patients with high-grade serous epithelial ovarian cancer and an exceptional response to platinum. We expect that we can identify at least 24 mutations in strong candidate repair genes that may affect the platinum response through their impact on DNA crosslink repair. We will test 24 recurrent mutations for their impact on ovarian cancer risk in a large case-control study including 2,000 ovarian cancer cases. We will furthermore test up to 24 genes with individually rare mutations for their impact on ovarian cancer risk in a large amplicon sequencing study of the same series of ovarian cancer cases. We will also sequence the exomes of ovarian tumours for somatic mutations in up to 50 patients for whom no candidate gene has been obtained in the germline exome. From the combined analyses of these approaches we will select a final set of 20 mutations for functional assessments through genome editing in immortalized normal ovarian epithelial cell lines. Wildtype and mutant counterparts will be comparatively tested for their DNA damage response and their drug response towards platinum. We expect that these studies will identify new ovarian cancer susceptibility genes and provide insights into their magnitudes of risk, their functional role and their predictive value for platinum-based therapy of malignancies.

相当大比例的卵巢癌发病率归因于遗传性生殖系突变。大约15%的卵巢癌患者携带BRCA1和BRCA2的胚系突变，最近发现的卵巢癌易感基因中还有额外的遗传变异，其中BRIP1、RAD51C和RAD51D的数据最全面。然而，很大一部分家族性卵巢癌聚集性仍不能用已知的种系突变来解释。鉴于以家族为基础的研究未能确定更多的卵巢癌易感基因，有必要采用替代方法来发现新的遗传性卵巢癌基因。由于迄今已知的基因突变影响DNA交联和同源重组修复，我们假设对突变阴性的异常应答者的外显子组分析将极大地帮助识别先前未被评价的遗传性卵巢癌基因。在本项目中，我们旨在通过对100例对铂类异常反应的高级别浆液性上皮性卵巢癌患者的全外显子组测序来识别新的卵巢癌基因的遗传性突变。我们预计我们可以确定至少24个强候选修复基因的突变，这些突变可能通过影响DNA交联修复来影响白金反应。我们将在一项大型病例对照研究中测试24个反复发生的突变对卵巢癌风险的影响，其中包括2000例卵巢癌病例。此外，我们还将在同一系列卵巢癌病例的大规模扩增序列研究中，测试多达24个具有个别罕见突变的基因对卵巢癌风险的影响。我们还将对最多50名在种系外显子组中未获得候选基因的患者的卵巢肿瘤外显子组进行体细胞突变测序。从这些方法的联合分析中，我们将选择最后一组20个突变，通过基因组编辑在永生化的正常卵巢上皮细胞系中进行功能评估。野生型和突变型将接受DNA损伤反应和对铂的药物反应的比较测试。我们期望这些研究将确定新的卵巢癌易感基因，并对它们的风险大小、它们的功能作用以及它们对以铂为基础的恶性肿瘤治疗的预测价值提供见解。