Although the FRZB 324Gly
variant and FRZB 200Trp/324Gly
double-substitution haplotype have been shown to have decreased ability to antagonize Wnt signaling in vitro
), this study showed no association between the FRZB Arg324Gly
polymorphisms or haplotypes and the risk of colorectal cancer or adenoma overall. In a previously published study with a similar number of cancer cases (N = 659) but smaller number of controls (N = 607), Shanmugam et al.
found that FRZB 324Gly
homozygotes had a five-fold increased risk of colorectal cancer (OR =5.01, 95% CI: 1.71-14.63) (4
). Our study did not replicate this result (OR = 1.09, 95% CI: 0.44-2.72). Shanmugan et al.
also reported that the association was stronger for rectal cancer. We did not observe a positive association with rectal cancer in our study (OR = 0.62, 95% CI: 0.08-4.91); however, the number of rectal cancer cases in our study was small (n = 152) and only one case was homozygous for the FRZB 324Gly
variant, making inferences difficult. It is possible that differences in environmental factors between the study populations contributed to the heterogeneity in results observed. We did observe statistically significant interactions between the FRZB Arg324Gly
polymorphism and body mass index and aspirin/ibuprofen use; however, our sample size for colorectal cancer was small and we did not observe the similar interactions with colorectal adenoma.
In our study, we observed a borderline protective association for exclusively rectal adenoma with carriers of the T
allele at Arg200Trp
, but the association was slightly weaker and not statistically significant for the less restrictive outcome of at least one rectal adenoma and rectal cancer. No association was observed between the T
allele at Arg200Trp
and rectal cancer in a study conducted in Germany (OR = 0.98, 95% CI: 0.69-1.38) (4
). Thus, this subgroup finding should be interpreted with caution. Consistent with our study, Shanmugan et al. found no association with the FRZB Arg200Trp/Arg324Gly
Our study had several strengths and limitations. The large sample of colorectal adenoma and cancer cases allowed us to comprehensively evaluate the risk associated with a spectrum of colorectal neoplastic tumors, and we evaluated genetic variants that had been shown to have a functional effect on Wnt signaling. However, our study had limited power to detect a recessive genetic association, and it is possible that the positive association observed by Shanmugam et al. failed to replicate in our study due to the modest sample size for colorectal cancer and the fact that associations for adenoma may be different from those for cancer. Genetic variants associated with progression from adenoma to cancer or with colorectal cancers that arise de novo may not be associated with adenoma risk. In addition, our coverage of FRZB was not comprehensive. There may be other genetic variants within this genetic region that are related to risk which were not captured in our study.
Although we did not observe an association with the FRZB Arg200Trp or Arg324Gly polymorphisms and the risk of colorectal neoplasia, it is possible that other variants within FRZB or other genes within the Wnt signaling pathway may be associated with risk. Additional studies are needed to evaluate associations within this important pathway in colorectal carcinogenesis.