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。是 已经明确，DLBCL病因学和预后中存在驱动体细胞突变， 生殖细胞遗传易感性的研究事实上，候选基因关联研究的早期结果表明， NHL中免疫和凋亡基因的常见遗传变异有希望发挥作用。在上一次融资中， 在BCL2L11（BIM）、CASP9和APAF 1中，我们发现了与BCL2L11（BIM）、CASP9和APAF 1的风险增加相关的SNP。 我们的SPORE病例对照研究。对40例DLBCL患者肿瘤中的这些基因进行重测序， 新的基因组改变，在目标1中，我们提出了病原学和治疗意义的特点 这些新的突变与实验室为基础的研究。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的不可知策略，以识别额外的新风险 变体。我们将通过利用我们的SPORE参与大型国际淋巴瘤 DLBCL的流行病学（InterLymph）联合全基因组关联研究（GWAS）（> 5000例病例 和10，000对照）以及我们对配对肿瘤和 生殖系DLBCL病例（N=77）。GWAS能够识别常见的变异，NGS研究将 允许我们识别较低频率的变体，这里定义为0.5%到5%。在Aim中使用多级设计 2，我们建议鉴定与发生DLBCL风险相关的新的生殖系低频变异， 在目标3中，我们鉴定并验证了DLBCL关键基因中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中的作用和途径。 预后这项建议利用了我们的孢子的独特资源，国际淋巴GWAS，和我们的 DLBCL全外显子组NGS项目。我们拥有一支优秀的团队，拥有良好的业绩记录， 跨学科的遗传学工作在淋巴瘤，并已证明有能力整合遗传 流行病学与基于实验室的功能性工作。我们的研究建立在先前研究的几个新发现之上 期间，而且还扩大到填补DLBCL遗传流行病学的重要需求， 低频率生殖系变异风险的综合研究。低频变体，无论是单独 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，我们将确定基因中的新驱动突变， DLBCL肿瘤中的信号通路，可以为肿瘤生物学提供信息并确定新的治疗靶点。在 总之，作为第一个全面研究DLBCL的种系和体细胞遗传变异，我们 可能为淋巴瘤的发生提供新的和意想不到的见解，然后可以在临床上加以利用 用于风险评估、预后分层和确定新的治疗靶点。

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 germline 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.