Genetic polymorphisms in base-excision repair pathway genes and risk of breast cancer.
Impaired base-excision repair (BER) function can give rise to the accumulation of DNA damage and initiation of cancer. We evaluated whether genetic variation in six BER pathway genes (XRCC1, ADPRT, APEX1, OGG1, LIG3, and MUTYH) is associated with breast cancer risk in two large population-based case-control studies in the United States (3,368 cases and 2,880 controls) and Poland (1,995 cases and 2,296 controls). A detailed evaluation was first done in a subset of 1,898 cases and 1,514 controls with mouthwash DNA samples in the U.S. study. Significant findings were followed up in the remainder of the U.S. study population that provided cytobrush DNA samples and in the Polish study. Using data from U.S. study participants with mouthwash DNA, we found no significant overall association between breast cancer risk and XRCC1 R280H and R194W, ADPRT V726W, APEX1 D148E, OGG1 S326C, LIG3 R780H, or MUTYH 5' untranslated region. These data suggested a decreased risk for XRCC1Q399R homozygous variants compared with homozygous wild-type in premenopausal women, but these findings were not confirmed when data from cytobrush DNA samples were added [combined odds ratio (OR), 0.8; 95% confidence interval (95% CI), 0.6-1.1] or in the Polish study (OR, 1.0; 95% CI, 0.7-1.5). Meta-analyses based on our data and published data from studies of two single nucleotide polymorphisms in XRCC1 showed no evidence of an overall association between breast cancer risk and homozygous variants versus wild-type for Q399R (OR, 1.1; 95% CI, 1.0-1.2) or R194W (OR, 1.0; 95% CI, 0.7-1.8), although there was a suggestion for an association in Asian populations for Q399R (OR, 1.6; 95% CI, 1.1-2.4; P = 0.02). In conclusion, our results do not support that the polymorphisms evaluated in six BER pathway genes play a major role in breast carcinogenesis, particularly in Caucasian populations.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Rockville, Maryland, USA. yawei.zhang@yale.edu
Yawei
Y
Zhang
Polly A
PA
Newcomb
Kathleen M
KM
Egan
Linda
L
Titus-Ernstoff
Stephen
S
Chanock
Robert
R
Welch
Louise A
LA
Brinton
Jolanta
J
Lissowska
Alicja
A
Bardin-Mikolajczak
Beata
B
Peplonska
Neonila
N
Szeszenia-Dabrowska
Witold
W
Zatonski
Montserrat
M
Garcia-Closas
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D011044:Poland; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D017697:Premenopause; D012306:Risk; D014481:United States
D004268:DNA-Binding Proteins; D045643:DNA Repair Enzymes