Mutation Hotspots in the β-Catenin Gene: Lessons from the Human Cancer Genome Databases

Mutations in the β-catenin gene (CTNNB1) have been implicated in the pathogenesis of some cancers. The recent development of cancer genome databases has facilitated comprehensive and focused analyses on the mutation status of cancer-related genes. We have used these databases to analyze the CTNNB1 mutations assembled from different tumor types. High incidences of CTNNB1 mutations were detected in endometrial, liver, and colorectal cancers. This finding agrees with the oncogenic role of aberrantly activated β-catenin in epithelial cells. Elevated frequencies of missense mutations were found in the exon 3 of CTNNB1, which is responsible for encoding the regulatory amino acids at the N-terminal region of the protein. In the case of metastatic colorectal cancers, inframe deletions were revealed in the region spanning exon 3. Thus, exon 3 of CTNNB1 can be considered to be a mutation hotspot in these cancers. Since the N-terminal region of the β-catenin protein forms a flexible structure, many questions arise regarding the structural and functional impacts of hotspot mutations. Clinical identification of hotspot mutations could provide the mechanistic basis for an oncogenic role of mutant β-catenin proteins in cancer cells. Furthermore, a systematic understanding of tumor-driving hotspot mutations could open new avenues for precision oncology.