Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
PLoS Genet. 2013;9(1):e1003220. doi: 10.1371/journal.pgen.1003220. Epub 2013 Jan 17.
The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (P(LYM) = 3.89×10(-8), OR = 1.29) and rs948562 (P(LYM) = 5.85×10(-7), OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, P(NHL) = 5.72×10(-7)) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (P(FL) = 2.69×10(-12), OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.
淋巴瘤易感性的遗传学反映了构成这种广泛表型的疾病的明显异质性。然而，一些家族中观察到多种淋巴瘤亚型，这表明对这些病理上不同实体存在共同的遗传易感性途径。我们使用两阶段 GWAS 测试了 944 例淋巴瘤病例（包括 282 例家族病例）和 4044 例公共共享对照中的 530,583 个 SNP，随后对 1245 例病例和 2596 例对照中的 50 个 SNP 进行了基因分型。11q12.1 上的一个新区域与联合淋巴瘤（LYM）亚型有关。该区域中的 SNP 包括位于 LPXN 附近的 rs12289961（P(LYM)=3.89×10(-8)，OR=1.29）和 rs948562（P(LYM)=5.85×10(-7)，OR=1.29）。6p23 上一个新的非 HLA 区域中的 SNP(rs707824，P(NHL)=5.72×10(-7)) 提示与淋巴瘤易感性相关的新的 SNP。四个 SNP 都位于先前报道的 HLA 区域 6p21.32 上，与滤泡性淋巴瘤呈全基因组显著相关。与滤泡性淋巴瘤最显著相关的是 rs4530903（P(FL)=2.69×10(-12)，OR=1.93）。HLA 基因座附近的三个新 SNP(rs9268853、rs2647046 和 rs2621416) 显示了与该区域相关的 FL 遗传易感性的额外遗传变异。GWAS 中涉及的基因也被发现在淋巴母细胞系中为 cis-eQTL；这些区域中的候选基因已被证明与造血和免疫功能有关。这些结果显示了新的易感性区域和等位基因异质性，表明存在对共享和特定类型的淋巴恶性肿瘤易感性的途径。
