title: Comprehensive assessment of genetic variation of catechol-O-methyltransferase and breast cancer risk.
abstract: Because catechol-O-methyltransferase (COMT) catalyzes the addition of methyl groups to stabilize catechol estrogens that may induce DNA damage, genetic variants could influence breast cancer risk. To comprehensively characterize genetic variation in this gene, we selected haplotype-tagging single nucleotide polymorphisms (htSNP) in COMT. A total of 11 htSNPs (including COMT Val(158)Met) were selected based on the resequencing and dense genotyping approach of the Breast and Prostate Cancer Cohort Consortium. htSNPs were genotyped in a population-based, case-control study in Poland (1,995 cases and 2,296 controls). Individual SNPs were not significantly associated with risk. Haplotypes were estimated using the expectation-maximization algorithm. Overall differences in the haplotype distribution between cases and controls were assessed using a global score test. The TGAG haplotype (frequent in 4.3% of controls), in a linkage disequilibrium (LD) block that included the 3' untranslated region (UTR) of COMT, was associated with breast cancer risk (odds ratio, 1.29; 95% confidence interval, 1.06-1.58) compared with the most common haplotype TGAA; however, the global test for haplotype associations was not significant (P = 0.09). Haplotypes in another LD block, which included COMT Val(158)Met, were not associated with breast cancer risk (global P = 0.76). Haplotype-breast cancer risk associations were not significantly modified by hormonally related risk factors, family history of breast cancer, or tumor characteristics. In summary, our data does not support a substantial overall association between COMT haplotypes and breast cancer. The suggestion of increased risk associated with a haplotype in the 3' UTR of COMT needs to be confirmed in independent study populations.
authors.affiliation: Division of Cancer Epidemiology, National Cancer Institute, 6120 Executive Boulevard, EPS/7055, Rockville, MD 20852, USA. gaudetm@mail.nih.gov
authors.forename: Mia M
authors.initials: MM
authors.lastname: Gaudet
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.forename: Beata
authors.initials: B
authors.lastname: Peplonska
authors.forename: Louise A
authors.initials: LA
authors.lastname: Brinton
authors.forename: Robert
authors.initials: R
authors.lastname: Welch
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Alicja
authors.initials: A
authors.lastname: Bardin-Mikolajczak
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000032:analysis / Q000235:genetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D011044:Poland / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D014505:Urban Population
chemical_list: D020413:3' Untranslated Regions; D009363:Neoplasm Proteins; D002394:Catechol O-Methyltransferase