Abstract
BackgroundRisk of non-Hodgkin lymphoma (NHL) is higher among individuals with a family history or a prior diagnosis of other cancers. Genome-wide association studies (GWAS) have suggested that some genetic susceptibility variants are associated with multiple complex traits (pleiotropy).ObjectiveWe investigated whether common risk variants identified in cancer GWAS may also increase the risk of developing NHL as the first primary cancer.MethodsAs part of the Population Architecture using Genomics and Epidemiology (PAGE) consortium, 113 cancer risk variants were analyzed in 1,441 NHL cases and 24,183 controls from three studies (BioVU, Multiethnic Cohort Study, Women's Health Initiative) for their association with the risk of overall NHL and common subtypes [diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL)] using an additive genetic model adjusted for age, sex and ethnicity. Study-specific results for each variant were meta-analyzed across studies.ResultsThe analysis of NHL subtype-specific GWAS SNPs and overall NHL suggested a shared genetic susceptibility between FL and DLBCL, particularly involving variants in the major histocompatibility complex region (rs6457327 in 6p21.33: FL OR = 1.29, p = 0.013; DLBCL OR = 1.23, p = 0.013; NHL OR = 1.22, p = 5.9×E-05). In the pleiotropy analysis, six risk variants for other cancers were associated with NHL risk, including variants for lung (rs401681 in TERT: OR per C allele = 0.89, p = 3.7×E-03; rs4975616 in TERT: OR per A allele = 0.90, p = 0.01; rs3131379 in MSH5: OR per T allele = 1.16, p = 0.03), prostate (rs7679673 in TET2: OR per C allele = 0.89, p = 5.7×E-03; rs10993994 in MSMB: OR per T allele = 1.09, p = 0.04), and breast (rs3817198 in LSP1: OR per C allele = 1.12, p = 0.01) cancers, but none of these associations remained significant after multiple test correction.ConclusionThis study does not support strong pleiotropic effects of non-NHL cancer risk variants in NHL etiology; however, larger studies are warranted.
Highlights
Non-Hodgkin lymphoma (NHL) is the sixth most common incident cancer in the U.S [1]
We explored whether variants identified for specific non-Hodgkin lymphoma (NHL) subtypes are associated with overall NHL risk, and whether any such associations differ across ethnic groups
We first investigated nine previously published Genome-wide association studies (GWAS) risk variants for specific NHL subtypes for an association with overall NHL risk to test for a shared genetic susceptibility
Summary
Non-Hodgkin lymphoma (NHL) is the sixth most common incident cancer in the U.S [1]. immune suppression, autoimmune disorders and certain infectious agents have been identified as strong risk factors for NHL, common host characteristics are likely to be involved in the etiology of NHL [2]. Risk of NHL has been reported to be greater among individuals with a first-degree family history of hematopoietic cancers [3]. In searching for the shared genetic basis of disease, genome-wide association studies (GWAS) have discovered a number of risk variants that demonstrate associations with two or more complex traits (pleiotropy) [7]. A good example is the multiple cancer site associations reported for variants at 8q24 [10,11], a region where some lymphoid malignancies exhibit translocations and a common susceptibility SNP [12,13,14,15]. Risk of non-Hodgkin lymphoma (NHL) is higher among individuals with a family history or a prior diagnosis of other cancers. Genome-wide association studies (GWAS) have suggested that some genetic susceptibility variants are associated with multiple complex traits (pleiotropy)
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