Abstract
Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13–1.43, p = 6.77×10−5), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34–0.77, p = 0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL.
Highlights
The incidence of non-Hodgkin’s lymphoma (NHL) in the U.S has doubled over the past two decades
Study population In total, the study involved 1,297 non-Hodgkin’s lymphoma (NHL) cases from the combined resources at MSKCC, Dana Farber Cancer Institute (DFCI) and Hadassah-Hebrew University, Israel as well as 1,946 controls collected from the New York Cancer Project (NYCP), a study of 18,000 New York City residents originally designed to assess the role of environment and genetics in cancer risk, and described previously elsewhere [29,30,31]
The rare syndromes attributed to inherited mutations in DNA repair genes, such as ataxia talangiectasia (A-T; mutations in ATM) or Nijmegen breakage syndrome (NBS; mutations in NBS1) manifest with early onset lymphomas of various histological subtypes [42,43]
Summary
The incidence of non-Hodgkin’s lymphoma (NHL) in the U.S has doubled over the past two decades. Besides recently completed genome-wide association studies (GWAS) [5,6,7,8,9,10,11,12,13], the search for missing genetic susceptibility to lymphoma in the past decade involved the association analyses of common genetic variants in candidate molecular pathways putatively involved in lymphoma development. The two-stage design, thorough selection of DNA repair genes, assessment of genetic interactions, and identification of putatively functional variants by using public genomic and expression data are among the major innovations in our study, which provides yet another focused exploration of the role of DNA repair pathways in genetic susceptibility to NHL
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