FGFR2 polymorphisms and endometrial cancer risk

4683

Fibroblast growth factor receptor 2 (FGFR2) plays a critical role in cell growth and signaling. It is abundantly expressed in the adult endometrium and somatic activating mutations in FGFR2 are seen in ~16% of endometrioid endometrial cancers (Pollock, et. al., Oncogene 26:7158-762, 2007). Two recent genome-wide association studies identified alleles in FGFR2 associated with breast cancer risk (Hunter et al., Nat Genet 39:870-874, 2007; Easton et al., Nature 447, 1087-1093, 2007). Given the similar role estrogen plays as a risk factor in breast and endometrial cancers, and the involvement of FGFR2 activating mutations in endometrial cancer, we sought to determine whether variation in FGFR2 contributes to endometrial cancer risk.
 We examined 7 haplotype tagging SNPs in FGFR2 (rs4752566, rs2981428, rs1219648, rs1863741, rs1047100, rs2912760 and rs3750817) in 354 well-characterized Caucasian endometrial cancer patients (ages 26 - 92 years at diagnosis) and 384 Caucasian cancer-free controls. SNPs were genotyped using Pyrosequencing^TM.
 The rs1219648 allele tagging the LD block previously associated with breast cancer risk showed no evidence for association with endometrial cancer, nor did the rs2981428, rs1863741, rs4752566, rs1047100 and rs3750817 SNPs. rs2912760, however, showed a difference in allele frequency in cases and controls that approached statistical significance. The rs2912760 minor allele (A) was more common in cases (27%) than controls (23%) (Odds ratio 1.22, 95% CI 0.96-1.56 p=0.06). Among the cases there was no association between SNPs and patient body mass index, tumor grade, age-at-diagnosis or loss of DNA mismatch repair (tumor MSI), all of which are associated with estrogen levels in endometrial cancer patients. Our data indicate the FGFR2 susceptibility allele(s) associated with breast cancer are unlikely to play a role in endometrial cancer. The rs2912760 marker, from a LD block not associated with breast cancer risk, appears to contribute to risk for endometrioid endometrial cancer.
 This work was supported by RO1 CA71754, the Siteman Cancer Center Summer Student Program (AK) and the Washington University Summer Undergraduate Research Fellowship Program funded in part through the Howard Hughes Medical Institute (AK).