Polymorphisms in DNA double-strand break repair genes and breast cancer risk in the Nurses' Health Study
Jiali Han
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2
3
Susan E.Hankinson
1
2
4
Hardeep Ranu
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2
Immaculata De Vivo
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2
3
4
David J.Hunter
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1
2
3
4
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Harvard Center for Cancer Prevention, Harvard School of Public Health
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665 Huntington Avenue, Boston, MA 02115
,
USA
1
Department of Epidemiology
2
Prevention, Harvard School of Public Health
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Room 105, Building II, 665 Huntington Avenue, Boston, MA 02115
,
USA
3
Department of Nutrition
4
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School
,
181 Longwood Avenue, Boston, MA 02115
,
USA
Genetic polymorphisms in double-strand break repair genes may influence DNA repair capacity and, in turn, confer predisposition to breast cancer. We prospectively assessed the associations of candidate polymorphisms G31479A (R188H) in XRCC2, A4541G (50-UTR), A17893G (IVS5-14) and C18067T (T241 M) in XRCC3, and C299T (50-UTR) and T1977C (D501D) in Ligase IV with breast cancer risk in a nested case-control study within the Nurses' Health Study (incident cases, n 1004; controls, n 1385). We observed no overall associations of these six genotypes with breast cancer risk. Four common haplotypes in XRCC3 accounted for 99% of the chromosomes of the present study population. We observed that Ligase IV 1977C carriers were at increased breast cancer risk if they had a first degree family history of breast cancer (test for interaction, P 0.01). We observed that the XRCC2 R188H polymorphism modified the association of plasma a-carotene level and breast cancer risk (test for ordinal interaction, P 0.03); the significantly decreased risk seen overall for women in the highest quartile of plasma a-carotene was only present among 188H non-carriers (the top quartile versus the bottom quartile; multivariate odds ratio, 0.55; 95% confidence interval, 0.40-0.75). No significant interactions were seen between any of these polymorphisms and duration or dose of cigarette smoking. The gene-environment interaction data suggest that the subtle effects of some of these variants on breast cancer risk may be magnified in the presence of certain exposures.
Introduction
Hypersensitivity to ionizing radiation (IR) and deficient repair
of radiation-induced DNA damage have been implicated in the
development of breast cancer (13). Because DNA
doublestrand breaks (DSB) are induced by carcinogens such as IR,
Abbreviations: BMI, body mass index; CI, confidence interval; DSB,
double-strand breaks; HR, homologous recombination; IR, ionizing radiation;
LRT, likelihood ratio test; NHEJ, non-homologous end joining; NHS, Nurses
Health Study; OR, odds ratio; SSB, single-strand breaks; SNP, single
nucleotide polymorphism.
Carcinogenesis vol.25 no.2 # Oxford University Press; all rights reserved
deficiency in DNA DSB repair may contribute to IR
hypersensitivity and breast cancer susceptibility. In addition, the
involvement of the two major hereditary breast cancer
susceptibility genes, BRCA1 and BRCA2, in the DNA DSB repair
pathway also suggests that defects in this pathway may
contribute to the development of breast cancer (4,5).
In addition to IR, DSB can be induced by exogenous
agents, such as chemicals and chemotherapy, and
endogenous reactive oxygen species. DSB can also be generated as
products of blocked replication forks and programmed
rearrangements (6,7). Repair of DNA DSB is essential to the
maintenance of genomic integrity. Homologous
recombination (HR) and non-homologous end joining (NHEJ) are two
distinct mechanisms in the repair of DSB in mammalian
cells. In the HR pathway, the strand exchange is catalyzed
by RAD51 and facilitated by RAD52 through direct
interaction. Five RAD51 paralogs facilitate the formation of RAD51
foci in two distinct complexes, XRCC3RAD51C and
RAD51BRAD51CRAD51DXRCC2 (8). Hamster cells
deficient in XRCC2 or XRCC3 exhibited defects in Rad51
focus formation (9,10), a decrease in HR induced by DSB
(11,12), hypersensitivity to radiation, increased spontaneous
chromosome aberrations and increased chromosome
missegregation (1315), implying critical roles of XRCC2 and
XRCC3 in HR. Deficiency in BRCA1 or BRCA2 showed
similar phenotypes (1619), suggesting potential roles of
XRCC2 and XRCC3 of HR in the development of breast
cancer. In the NHEJ pathway, the termini of DSB are
bound by the complex of the Ku70 and Ku80 heterodimer
and DNA-dependent protein kinase and the break is repaired
by the complex of Ligase IV and XRCC4 (6). Inactivation of
the Ligase IV gene in mice led to embryonic lethality; these
mouse cells showed increased sensitivity to IR and defects in
V(D)J joining (20,21).
Genetic polymorphisms in DSB repair genes may have
subtle effects on DNA repair capacity and confer
predisposition to breast cancer. Two casecontrol studies among
European Caucasians provided some preliminary evidence
that genetic variants in XRCC2, XRCC3 and Ligase IV may
be associated with breast cancer risk (22,23). We prospectively
evaluated the associations between candidate polymorphisms
i (...truncated)