Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies.
Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies.
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DOI：
10.1371/journal.pgen.1003220
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Offit K
中科院分区：
文献类型：
--
作者：
Vijai J;Kirchhoff T;Schrader KA;Brown J;Dutra-Clarke AV;Manschreck C;Hansen N;Rau-Murthy R;Sarrel K;Przybylo J;Shah S;Cheguri S;Stadler Z;Zhang L;Paltiel O;Ben-Yehuda D;Viale A;Portlock C;Straus D;Lipkin SM;Lacher M;Robson M;Klein RJ;Zelenetz A;Offit K
淋巴瘤易感性的遗传学反映了包括这种广泛表型的疾病的显著异质性。然而，在一些家族中观察到多种淋巴瘤亚型，这表明这些病理学不同实体的遗传易感性有共同的途径。使用两阶段GWAS，我们在944例淋巴瘤患者中检测了530，583个SNP，包括282例家族性病例和4，044例公共共享对照，然后在1，245例病例和2，596例对照中对50个SNP进行基因分型。11q12.1上的一个新区域与联合淋巴瘤（LYM）亚型相关。该区域的SNP包括LPXN附近的rs 12289961（PLYM = 3.89×10−8，OR = 1.29）和rs 948562（PLYM = 5.85×10−7，OR = 1.29）。 6p 23上一个新的非HLA区域的SNP（rs707824，PNHL = 5.72×10−7）提示与淋巴瘤易感性相关。 4个SNPs，都在以前报道的HLA区域，6p21.32，显示全基因组与滤泡性淋巴瘤显著相关。rs 4530903与滤泡性淋巴瘤最显著相关（PFL = 2.69×10−12，OR = 1.93）。 HLA基因座附近的三个新的SNPs，rs 9268853，rs 2647046和rs 2621416，表现出额外的变异，有助于与该区域相关的FL的遗传易感性。GWAS所涉及的基因也被发现是淋巴母细胞系中的顺式eQTL;这些区域中的候选基因与造血和免疫功能有关。这些结果，显示新的易感区域和等位基因的异质性，点的存在的途径的敏感性，以共享以及特定亚型的淋巴恶性肿瘤。B细胞淋巴瘤包括代表免疫细胞在不同成熟阶段的异常增殖的几种疾病。不同亚型的淋巴瘤可能有不同的病因和致病机制，反映了这些疾病不同的组织学和临床特征。本研究旨在确定淋巴瘤的共同和特定遗传风险因素。利用全基因组方法，我们发现了与淋巴恶性肿瘤风险相关的基因组中的新位置。这些区域的常见变异，在染色体11q12.1和6p 23上，每个都与淋巴瘤风险的适度改变相关。这些区域含有几个在淋巴成熟和功能中具有生物学重要性的基因。我们还进一步描述了6p21.32的HLA区域，该区域以前与淋巴瘤风险相关，并被认为在免疫功能中很重要。一些相关的SNP标记物特异于一种常见的淋巴瘤亚型，例如滤泡性淋巴瘤。然而，其他人与疾病的组合子集相关，这表明常见遗传变异与人类淋巴癌之间存在共享和亚型特异性关联。二次分析表明，这两个新的区域具有生物学相关的候选者，并调节细胞发育和造血。
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, (PLYM = 3.89×10−8, OR = 1.29) and rs948562 (PLYM = 5.85×10−7, OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, PNHL = 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 (PFL = 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. B-cell lymphomas comprise several diseases representing aberrant proliferations of immune cells at various stages of maturation. It might be expected that dissimilar subtypes of lymphoma will have different etiologic and pathogenic mechanisms, reflecting the distinct histologic and clinical characteristics of these diseases. This study aims to define both shared as well as specific genetic risk factors for lymphoma. Utilizing a genome-wide approach, we discovered novel locations in the genome associated with risk for lymphoid malignancies. Common variants in these regions, on chromosome 11q12.1 and 6p23, were each associated with a modest modification of risk for lymphoma. These regions harbor several genes of biological importance in lymphoid maturation and function. We also further characterized the HLA region at 6p21.32, previously associated with lymphoma risk and thought to be important in immune function. Some of the associated SNP markers were specific for one common subtype of lymphoma, e.g. follicular lymphoma. However, others were associated with combined subsets of disease, suggesting that there are both shared and subtype-specific associations between common genetic variants and human lymphoid cancer. Secondary analyses showed that the two novel regions harbor candidates that are biologically relevant and that regulate cell development and hematopoiesis.
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