Resequencing and Functional Studies to Identify Causal Gene Variants of Lymphoma

描述（由申请人提供）：非霍奇金淋巴瘤（NHL）是美国第五大常见癌症，也是全球头号血液恶性肿瘤。NHL对发病率和死亡率有重大影响;因此，导致鉴定致病基因变异的研究将有助于通过更好的筛查来鉴定高危个体;提供重要线索来鉴定可能适合治疗调节的生物学途径/靶点;并为有益于淋巴瘤研究的研究提供新方向。为了实现这一点，基于全基因组关联研究，对已知与NHL相关的靶基因组区域进行重测序，然后在大型、良好表型研究（如联合体）中验证潜在的因果SNP是至关重要的，这将有助于建立真正的因果遗传变异。对致病基因变异的进一步表征也至关重要。基于两个NHL GWAS的发现，主要组织相容性复合体（MHC）区域染色体带6p21.32-33上的SNP和HLA等位基因与NHL的主要亚型之一滤泡性淋巴瘤（FL）的风险相关。我们的GWAS表明，一个重要的遗传作用存在FL. MHC区域以前已被链接到一些自身免疫性疾病，这表明他们可能与FL共享共同的风险等位基因。InterLymph成员的研究已经确定了额外的易感基因座，一些以外的MHC，已在财团内验证。因此，有一个强大的动力，以确定致病基因变异已知影响FL和其他NHL亚型的风险，因为没有这种研究淋巴瘤已经进行。为了实现这一目标，将进行以下目标：在目标1中，将实施靶向DNA捕获和下一代测序，以识别MHC和与FL相关的其他区域中的所有基因变异（罕见和常见的SNP和结构变异）。DNA已经从NHL的两项大型基于人群的病例对照研究中提取。一旦在研究人群中鉴定出新的和已知的SNP并检测其与FL的相关性，将进行计算机功能分析以预测因果SNP。在目标2中，将在NHL流行病学研究国际研究者联盟（InterLymph）内的独立病例对照研究中对puplatin功能SNP进行基因分型。在目标3中，将在非裔美国人FL病例中评估HLA等位基因型和SNP，以帮助解决欧洲人群中MHC内的高LD问题。在目标4中，将对经验证的SNP进行功能表征。越来越多的证据支持MHC中的遗传变异与许多自身免疫性疾病的风险的作用。因此，在这个区域的淋巴瘤的致病基因变异的鉴定也可能有助于了解其他疾病共享共同的易感基因座。

DESCRIPTION (provided by applicant): Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and the number one hematological malignancy worldwide. NHL has a major impact on morbidity and mortality; thus, studies that lead to the identification of causal gene variants will help to identify at-risk individuals through better screening; provide important clues to identify biological pathways/targets that may be amenable to therapeutic modulation; and provide new directions for studies that benefit lymphoma research. To accomplish this, resequencing targeted genomic regions known to be associated with NHL based on genome-wide association studies, followed by validation of potentially causal SNPs in large, well-phenotyped studies (such as in a consortium) is of utmost importance and will help to establish true causal genetic variants. Further characterization of causal gene variants is also crucial. Based on findings from two GWAS of NHL, SNPs and HLA alleles on chromosome band 6p21.32-33 in the major histocompatibility complex (MHC) region were associated with risk of follicular lymphoma (FL), one of the major subtypes of NHL. Our GWAS suggests an important genetic role exists for FL. MHC regions have been previously linked to some autoimmune disorders suggesting that they may share common risk alleles with FL. InterLymph member studies have identified additional susceptibility loci, some outside of the MHC, that have been validated within the consortium. Thus, there is a strong impetus to identify causal gene variants known to affect risk of FL and other NHL subtypes since no studies of this kind for lymphoma have been performed. To accomplish this, the following Aims will be undertaken: In Aim 1, targeted DNA capture and next generation sequencing will be implemented to identify all gene variants (rare and common SNPs and structural variants) in the MHC and in other regions associated with FL. The DNA has already been extracted from two large population-based case-control studies of NHL. Once novel and known SNPs are identified and tested for association with FL in the study populations, in silico functional analysis will be undertaken to predict causal SNPs. In Aim 2, putatively functional SNPs will be genotyped in independent case-control studies within the International Consortium of Investigators Working on NHL Epidemiologic Studies (InterLymph). In Aim 3, HLA allelotypes and SNPs will be assessed in African-American FL cases to help address the issue of high LD in European populations within the MHC. In Aim 4, validated SNPs will be functionally characterized. Accumulating evidence supports the role of genetic variation in the MHC with risk of many autoimmune diseases. Thus, the identification of causal gene variants in this region for lymphoma may also prove helpful in understanding other diseases sharing common susceptibility loci.