Genetic Epidemiology and Function of Germline and Somatic Variants in DLBCL

弥漫性大B细胞淋巴瘤(DLBCL)是最常见的非霍奇金淋巴瘤(NHL)亚型。它是 众所周知，在DLBCL的病因和预后中存在驱动因素的体细胞突变，以及它在其中的作用 生殖系遗传易感性。事实上，候选基因关联研究的早期结果表明 常见基因变异在非霍奇金淋巴瘤免疫和凋亡基因中的作用前景看好。在上一笔资金中 周期中，我们发现BCL2L11(BIM)、CASP9和APAF1中的SNP与糖尿病风险增加相关 我们的孢子病例对照研究。40例DLBCL患者肿瘤中这些基因的重新测序 新的基因组改变，在目标1中，我们建议表征病因学和治疗意义 这些新的突变与基于实验室的研究。在目标2和目标3中，我们提出了一个全面和 整合体细胞和生殖系遗传学以识别额外的新风险的不可知性策略 变种。我们将利用我们的孢子在大型国际淋巴瘤中的参与来做到这一点 DLBCL(&GT；S000例)的流行病学(淋巴)联盟全基因组关联研究 和10,000个对照)和我们的配对肿瘤和 生殖系DLBCL(N=77例)。GWAS被授权识别常见的变种，而NGS的研究将 使我们能够识别较低频率的变种，这里定义为0.5%至5%。在AIM中使用多阶段设计 2，我们建议确定与DLBCL发生风险相关的新的Gennline低频变异， 在目标3中，我们识别和验证了对DLBCL至关重要的基因的体细胞获得性驱动突变 发病机制。在探索性分析中，我们将评估这些变异在DLBCL中的途径和作用 预后。这一建议利用了我们独特的孢子资源，InterLymph Gwas和我们的 DLBCL全外延NGS项目。我们拥有一支出色的团队，在以下方面有着良好的记录 淋巴瘤的跨学科遗传学工作，并展示了整合基因的能力 以实验室为基础的功能工作的流行病学。我们的研究建立在先前研究的几个新发现的基础上 期间，还扩大到填补了DLBCL作为第一个遗传流行病学的重要需求 风险中低频率生殖系变异的综合研究。低频变种，或者单独 或累积在一个基因上，并与常见的变异相结合，可能会告知病因学 路径和临床风险评估。此外，我们将识别基因和基因中的新驱动突变 DLBCL肿瘤的途径可以为肿瘤生物学提供信息并识别新的治疗靶点。在……里面 总结，作为对DLBCL生殖系和体细胞遗传变异的第一次全面研究，我们是 可能为淋巴增生症提供新的和意想不到的见解，然后可以用于临床 用于风险评估、预后分层和确定新的治疗目标。

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) subtype. It is well established that there are driver somatic mutations in DLBCL etiology and prognosis, as well as a role for germline genetic susceptibility. In fact, early results from candidate gene association studies have shown a promising role for common genetic variants in immune and apoptotic genes in NHL. In the last funding cycle, we identified SNPs in BCL2L11 (BIM), CASP9, and APAF1 that were associated with increased risk in our SPORE case-control study. Resequencing of these genes in the tumors of 40 DLBCL patients identified novel genomic alterations, and in Aim 1 we propose to characterize the etiologic and therapeutic significance of these novel mutations with laboratory-based studies. In Aim 2 and 3, we propose a comprehensive and agnostic strategy that integrates both somatic and germline genetics in order to identify additional novel risk variants. We will do this by leveraging our SPORE's involvement in the large International Lymphoma Epidemiology (InterLymph) consortium genome-wide association study (GWAS) of DLBCL (>S000 cases and 10,000 controls) and our whole-exome next generation sequencing (NGS) study of paired tumor and germline DLBCL cases (N=77). The GWAS is powered to identify common variants, and the NGS study will allow us to identify lower frequency variants, defined here as 0.5% to 5%. Using a multistage design in Aim 2, we propose to identify novel gennline low-frequency variants associated with risk of developing DLBCL, and in Aim 3, we identify and validate somatically acquired driver mutations in genes critical to DLBCL pathogenesis. In exploratory analyses, we will evaluate pathways and the role of these variants in DLBCL prognosis. This proposal utilizes the unique resources of our SPORE, the InterLymph GWAS, and our DLBCL whole-exome NGS project. We have an outstanding team with a strong track record of interdisciplinary genetics work in lymphoma and have demonstrated the ability to integrate genetic epidemiology with lab-based functional work. Our study builds on several novel findings from the prior study period, but also expands to fill an important need in the genetic epidemiology of DLBCL as the first comprehensive study of low frequency germline variants in risk. Low frequency variants, either individually or cumulatively across a gene, and in combination with common variants, are likely to inform etiologic pathways and clinical risk assessment. Furthermore, we will identify novel driver mutations in genes and pathways from DLBCL tumors that can inform tumor biology and identify novel treatment targets. In summary, as the first comprehensive study of both germline and somatic genetic variants in DLBCL, we are likely to provide new and unexpected insights into lymphomagenesis, which can then be exploited clinically for risk assessment, prognostic stratification and identification of new treatment targets.