Analysis of a Germline AXIN2 Variant in Tumorigenesis

The Wnt signaling pathway is critical for normal development and proliferation, but over-active Wnt signaling has an established role in many cancers, including hereditary colorectal cancer syndromes. AXIN2 is a gene that encodes a negative regulator of Wnt/beta-catenin signaling, and has recently been proposed as a target for small molecule therapeutics. Because of its inhibitory role in Wnt signaling, AXIN2 has been long considered a tumor suppressor. Interestingly, some studies suggest that rather than suppressing tumor formation, AXIN2 might act in a pro-cancer genetic program.

 A family seen at the University of Michigan for evaluation of features including polyposis and premature breast and colon cancer was found to carry a germline AXIN2 mutation. This mutation is predicted to truncate synthesis of the AXIN2 protein. This AXIN2 mutation is similar to both a germline mutation previously described in another family and the somatic mutations seen in some colon cancers. In vitro studies of the mutant protein (trAXIN2) have found that trAXIN2 assembles into beta-catenin destruction complexes and inhibits colony formation in colon cancer cell lines, similar to wild-type. However, trAXIN2 has reduced function in the inhibition of Wnt/beta-catenin target genes and in a zebrafish model, the trAXIN2 protein creates a more severe developmental phenotype. In the family, this mutation is heterozygous, so the allele could predispose to cancer by haploinsufficiency or through a loss of function mechanism. The functional significance of the germline AXIN2 mutation will continue to be explored with cell-based assays and a mouse model of the human mutation.