title: Genetic variation in DNA repair pathways and risk of non-Hodgkin's lymphoma.
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.
authors.affiliation: NYU School of Medicine, New York University, New York, New York, United States of America.
authors.forename: Justin
authors.initials: J
authors.lastname: Rendleman
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Antipin
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Boris
authors.initials: B
authors.lastname: Reva
authors.affiliation: NYU School of Medicine, New York University, New York, New York, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Adaniel
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Przybylo
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Ana
authors.initials: A
authors.lastname: Dutra-Clarke
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Nichole
authors.initials: N
authors.lastname: Hansen
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Kety
authors.initials: K
authors.lastname: Huberman
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Borsu
authors.affiliation: Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ora
authors.initials: O
authors.lastname: Paltiel
authors.affiliation: Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Ben-Yehuda
authors.affiliation: Dana Farber Cancer Center, Harvard University, Boston, Massachusetts, United States of America.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Dana Farber Cancer Center, Harvard University, Boston, Massachusetts, United States of America.
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Freedman
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zelenetz
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Klein
authors.affiliation: NYU School of Medicine, New York University, New York, New York, United States of America.
authors.forename: Yongzhao
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Mortimer
authors.initials: M
authors.lastname: Lacher
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vijai
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.affiliation: NYU School of Medicine, New York University, New York, New York, United States of America.
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhoff
mesh_terms: D004260:DNA Repair / Q000235:genetics*; D004843:Epistasis, Genetic / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics