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Polymorphisms in DNA repair genes, recreational physical activity and breast cancer risk
Author(s) -
McCullough Lauren E.,
Santella Regina M.,
Cleveland Rebecca J.,
Millikan Robert C.,
Olshan Andrew F.,
North Kari E.,
Bradshaw Patrick T.,
Eng Sybil M.,
Terry Mary Beth,
Shen Jing,
Crew Katherine D.,
Rossner Pavel,
Teitelbaum Susan L.,
Neugut Alfred I.,
Gammon Marilie D.
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28383
Subject(s) - msh2 , mlh1 , breast cancer , dna mismatch repair , dna repair , nucleotide excision repair , biology , genetics , cancer research , base excision repair , cancer , medicine , oncology , gene
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.