Whole Genome Sequencing to Discover Familial Myeloma Risk Genes

描述（申请人提供）：多发性骨髓瘤是来源于生发后中心B细胞的单克隆浆细胞的恶性增殖。骨髓瘤细胞产生单克隆副蛋白并引起溶解性骨病变、贫血和肾衰竭。骨髓瘤几乎占所有血液学癌症的14%。尽管深入研究，多发性骨髓瘤的病因尚不清楚。骨髓瘤病例的大量家族聚集性报告已经被报道，包括我们自己的团队。这些数据与家族性骨髓瘤和相关恶性肿瘤易感性的特定风险基因的存在是一致的。与影响治疗决策（手术管理和PARP抑制剂）、监测（年度乳房MRI）和预防（卵巢切除术）的BRCA1乳腺癌构成风险基因类似，家族性骨髓瘤风险基因的鉴定可能提供重要的新机制见解，也可能显著影响受影响个体和高危家庭成员的重要临床决策。不幸的是，目前还没有已知的遗传性或散发性骨髓瘤风险基因。在这里，我们将使用一种创新的策略，结合以前未开发的计算资源，在世界上最大的家族性骨髓瘤临床和遗传资源之一中发现并严格验证新的体质癌症风险基因。我们将使用一种创新的分层全外显子组和全基因组测序策略，充分表征家族性骨髓瘤先显子和可用的生物标本，以帮助发现、优先考虑和验证候选的致病性结构突变。我们的总体目标是发现并确认第一个宪法家族

DESCRIPTION (provided by applicant): Multiple Myeloma is a malignant proliferation of monoclonal plasma cells that are derived from post-germinal-center B cells. Myeloma cells produce monoclonal paraproteins and cause lytic bone lesions, anemia and renal failure. Myeloma accounts for almost 14% of all hematologic cancers. Despite intensive study, the etiology of Multiple Myeloma is unknown. Reports of substantial familial clustering of myeloma cases have been reported, including by our own team. These data are consistent with the existence of specific risk genes that predispose to Familial Myeloma and associated malignancies. Analogous to the BRCA1 breast cancer constitutional risk gene, which affects treatment decisions (surgical management and PARP inhibitors), surveillance (annual breast MRI) and prevention (oophorectomy), identification of Familial Myeloma risk genes is likely to provide important new mechanistic insights that can also significantly impact important clinical decision making for both affected individuals and at-risk family members. Unfortunately, there are currently no known constitutional familial or sporadic myeloma risk genes. Here, we will use an innovative strategy incorporating previously untapped computational resources to discover and rigorously validate novel constitutional cancer risk genes in one of the largest Familial Myeloma clinical and genetic resources in the world. We will use an innovative tiered whole exome and full genome sequencing strategy of well- characterized Familial Myeloma probands and available biospecimens to help discover, prioritize and validate causative constitutional mutation candidates. Our overall goal is to discover and validate the first constitutional Familial Myeloma risk genes in clinically well- characterized kindreds. This is anticipated to increase the number of patients and their at-risk family members who can benefit from increased cancer surveillance, early detection and cancer prevention.