We did not observe a significant association between seven novel breast cancer susceptibility alleles and risk of epithelial ovarian cancer in this large combined study population. There was also no clear evidence of gene-gene or gene-environment interactions, or associations with the major histologic subtypes of ovarian cancer.
In genome-wide association studies by Hunter et al. and Easton et al., two SNPs in intron 2 of FGFR2
were most strongly associated with breast cancer risk.3, 4
gene encodes fibroblast growth factor receptor 2, a transmembrane tyrosine kinase involved in cell signaling and development of the embryonic mammary gland and other tissues.12, 13
Although polymorphisms in the FGFR2
gene have not been examined previously in relation to ovarian cancer risk, Huijts et al. reported a borderline significant association (p
=0.05) between FGFR2
SNP rs2981582 and the proportion of first- or second-degree female relatives with a history of breast or ovarian cancer.6
In addition, Steele and colleagues reported that FGFR2 isoform IIIb was expressed in epithelial ovarian cancers but not in the normal ovarian surface epithelium and that ligands to FGFR2-IIIb promoted proliferation and prevented apoptosis of ovarian cancer cells.14, 15
Although the FGFR2
polymorphisms were not associated with ovarian cancer risk in our study, we cannot rule out the possibility that other polymorphisms in the FGFR2
gene may influence ovarian cancer risk, or that FGFR2 may otherwise be involved in ovarian carcinogenesis.
With the exception of rs13281615 in chromosome 8q24, the other SNPs included in our analysis have not previously been examined in relation to risk of ovarian cancer. In the breast cancer genome-wide association study by Easton and colleagues, the estimated OR for each one-unit increase in the number of minor alleles was 1.13 for rs889312 (MAP3K1
), 1.07 for rs3817198 (LSP1
), 1.08 for rs13281615 (chromosome 8q24), and 1.20 for rs3803662 (TNRC9
In the study by Stacey and colleagues, the corresponding ORs were 1.28 for rs3803662 (TNRC9
) and 1.20 for rs13387042 (chromosome 2q35).5
It is possible that one or more of these SNPs increases ovarian cancer risk but that our power was insufficient to detect the association. In a recent study by Ghoussaini et al., nine SNPs in 8q24 were associated with risk of one or more of the cancers examined (colorectal, ovarian, breast, or prostate), but none of the SNPs was associated with all four cancers. The SNP included in our analysis (rs13281615) was associated with breast cancer risk but not risk of colorectal, ovarian, or prostate cancer, while three other SNPs (rs10505477, rs10808556, and rs6983267) within a single haplotype block were associated with risk of colorectal, ovarian, and prostate cancer but not risk of breast cancer.16
These results suggest that different risk alleles within the same gene or chromosomal region may be associated with different cancers and that, despite the lack of an association with the SNPs included in our analysis, other SNPs in these genes and chromosomal regions may be associated with ovarian cancer risk. Although there is little evidence suggesting a role of the MAP3K1
, and TNRC9
genes or 2q35 in ovarian carcinogenesis, analyses of additional SNPs in these regions, as well as analyses in larger study populations, would be helpful to further evaluate these associations.
Strengths of this study include the large number of cases in the combined study population, the examination of each association in two independent populations, and the availability of covariate data for analyzing gene-environment interactions. However, although our pooled analysis included almost 1,400 cases, we had insufficient power to detect very weak associations, gene-gene and gene-environment interactions, and associations with histologic subtypes of ovarian cancer. The participation rates in the NECC may have influenced our results if the cases or controls enrolled in the study differed from the population of eligible participants; however, the similar results in the NECC and the NHS, where the cases and matched controls were part of a large prospective cohort of women with excellent participation throughout the follow-up period, suggests that selection bias did not have a major impact on our results.
In conclusion, our results do not support modest or strong associations between seven novel breast cancer susceptibility alleles and risk of epithelial ovarian cancer. This suggests that the risk alleles identified in the breast cancer genome-wide scans to date may be specific to breast cancer and may not be associated more generally with risk of female reproductive cancers.