title: Polymorphisms in DNA repair genes, recreational physical activity and breast cancer risk.
abstract: The mechanisms driving the inverse association between recreational physical activity (RPA) and breast cancer risk are complex. While exercise is associated with increased reactive oxygen species production it may also improve damage repair systems, particularly those that operate on single-strand breaks including base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR). Of these repair pathways, the role of MMR in breast carcinogenesis is least investigated. Polymorphisms in MMR or other DNA repair gene variants may modify the association between RPA and breast cancer incidence. We investigated the individual and joint effects of variants in three MMR pathway genes (MSH3, MLH1 and MSH2) on breast cancer occurrence using resources from the Long Island Breast Cancer Study Project. We additionally characterized interactions between RPA and genetic polymorphisms in MMR, BER and NER pathways. We found statistically significant multiplicative interactions (p < 0.05) between MSH2 and MLH1, as well as between postmenopausal RPA and four variants in DNA repair (XPC-Ala499Val, XPF-Arg415Gln, XPG-Asp1104His and MLH1-lle219Val). Significant risk reductions were observed among highly active women with the common genotype for XPC (OR = 0.54; 95% CI, 0.36-0.81) and XPF (OR = 0.62; 95% CI, 0.44-0.87), as well as among active women who carried at least one variant allele in XPG (OR = 0.46; 95% CI, 0.29-0.77) and MLH1 (OR = 0.46; 95% CI, 0.30-0.71). Our data show that women with minor alleles in both MSH2 and MLH1 could be at increased breast cancer risk. RPA may be modified by genes in the DNA repair pathway, and merit further investigation.
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: McCullough
authors.forename: Regina M
authors.initials: RM
authors.lastname: Santella
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Cleveland
authors.forename: Robert C
authors.initials: RC
authors.lastname: Millikan
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Olshan
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Bradshaw
authors.forename: Sybil M
authors.initials: SM
authors.lastname: Eng
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Terry
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Crew
authors.forename: Pavel
authors.initials: P
authors.lastname: Rossner
authors.forename: Susan L
authors.initials: SL
authors.lastname: Teitelbaum
authors.forename: Alfred I
authors.initials: AI
authors.lastname: Neugut
authors.forename: Marilie D
authors.initials: MD
authors.lastname: Gammon
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology; D063646:Carcinogenesis; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D009043:Motor Activity; D020641:Polymorphism, Single Nucleotide; D011998:Recreation
keywords: DNA repair; breast cancer; epidemiology; mismatch repair; physical activity