Wingless-type frizzled protein receptor signaling and its putative role inhuman colon cancer

We wish to identify new candidate genes involved in the pathogenesis of hum an colon cancer to better understand the diversity of phenotype presentatio n that varies from individual to individual. Our working hypothesis is that genetic polymorphism of genes in the Wingless-type (Wnt) frizzled protein receptor pathway is associated with the susceptibility to develop colon can cer. The putative role of the Wnt pathway in sporadic human malignancy of t he colon suggests involvement in inherited cancer as well. beta -catenin is the crucial messenger in frizzled receptor signaling, transmitting Wnt-lig and signals such as signals from secreted apoptosis-related proteins to the nucleus, it functions as a genome denunciator by initiating amplification of oncogenes. The net effect of beta -catenin depends on the magnitude of i ts accumulation in the cytoplasm and, therefore, upon expression profiles o f genes in the Wnt pathway. We propose that Variations in allelic frequenci es of genes involved in the beta -catenin cascade may either promote or imp ede malignant transformation of the colon. If certain polymorphisms in Wnt signaling through beta -catenin predispose to colon cancer, this might mani fest as decreased binding affinity of proteins such as axin or the adenomat ous polyposis coil protein to beta -catenin. Association studies are propos ed to test the hypothesis, which could serve as an initial step toward unde rstanding the complexity of tumor biology. The clinical rationale in unrave ling the genetic susceptibility to cancer lies in identification of a subgr oup of individuals who may benefit from beta -catenin targeting agents, whi ch could potentially overcome this genetic instability. (C) 2001 Wiley-Liss , Inc.