Abstract
We recently reported a differential association of parity with breast cancer incidence according to hormone receptor status among African American (AA) women, with higher parity associated with a reduced risk of estrogen receptor positive (ER+)/ progesterone receptor positive (PR+) breast cancer and an increased risk of ER−/PR− breast cancer. To elucidate mechanisms for the difference by breast cancer subtype, we examined interactions of parity status with specified genetic polymorphisms that have been identified as breast cancer loci in genome-wide association studies (GWAS). SNPs in three loci were assessed: intron 2 in the FGFR2 gene, which was the most strongly associated of all breast cancer GWAS loci and appears to be most important for ER+ breast cancer; the chromosome 5p12 region, which may also be restricted to ER+ cancer and was replicated in our study of AA women; and the TOX3/LOC643714 locus, which was also replicated in our study. We analyzed data from the Black Women's Health Study, a prospective follow-up study of 59,000 AA women from across the US who enrolled in 1995 and have been followed since then by biennial questionnaires. Incident breast cancer cases are confirmed and characterized as to ER/PR status by review of pathology data. Saliva samples were provided by approximately 27,000 participants through the mouthwash-swish method. Genotyping was conducted on the Sequenom Mass-Array iPLEX technology as part of a project to test index SNPs from European ancestry GWAS as well as other tagSNPs in each region. An average reproducibility of 99% was obtained among blinded duplicates; all SNPs with calling rate <90% and all samples with calling rate <80% were excluded. Mean call rate in the final data set for both SNPs and samples was 99.0%. Genotyping results and questionnaire data on parity and other established risk factors were available for 650 incident breast cancer cases and 1770 controls matched on year of birth and region of residence. Odds ratios for the joint association of genotype and parity and for the association of parity with breast cancer within genotype were carried out by logistic regression controlling for age, region, percent European ancestry (computed from genotype data on a set of validated Ancestry Informative Markers), family history of breast cancer, age at menarche, age at first birth, and body mass index. There was not a significant interaction of parity (0/1+) with the two TOX3/LOC643714 SNPs examined. Four SNPs in FGFR2, none of which had a significant overall association in the BWHS, were examined and an interaction with parity was observed for one, rs2981579 (p-interaction = 0.006). The per-allele odds ratio was 1.71 (1.17–2.49) among nulliparous women, whereas the comparable OR among parous women was 0.95 (0.81–1.13). Parity was associated with a reduced risk of breast cancer only among women who were homozygous for the risk allele A and this pattern appeared consistent for ER+/PR+ and ER-/PR-breast cancer. Three SNPs in chromosome 5p12 were examined and there was an overall interaction for one, rs4415084 (p-interaction = 0.03). The interaction was present only for ER+/PR+ tumors (p-interaction = 0.01). Parity was associated with a reduced risk of ER+ breast cancer among women homozygous for the C allele but not among women who carried one or more of the T risk alleles. Two large studies of European ancestry populations have found no significant interactions of reproductive factors with low-penetrance genetic polymorphisms. Smaller studies in Asian populations have found interactions of oral contraceptive use with FGFR2 variants and two independent U.S. studies showed an interaction of hormone replacement therapy with FGFR2 variants. The present results provide the first data on the interaction of parity with low-penetrance SNPs for breast cancer in AA women and, as such, need to be replicated in other data.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):B92.
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