To βor not to β: Lack of correlation between APC mutation and β-catenin nuclear localization in colorectal cancer

Colorectal cancer (CRC) appears to arise from sequential genetic lesions in tumor suppressor genes (APC, SMAD4 and TP53) and oncogenes (KRAS) leading to the classical adenoma to carcinoma progression. Biallelic APC inactivating genetic aberrations are detected in about 70% of early microadenomas implicating APC inactivation as the first genetic hit in CRC. APC is an essential protein of the Wnt destruction complex; APC inactivation is believed to cause disruption of the complex allowing stabilization and nuclear translocation of {beta}-catenin, resulting in transcriptional activation of cancer-promoting genes. Here, we provide evidence for a surprising lack of correlation between APC mutation and {beta}-catenin nuclear localization in early-onset sporadic rectal cancer samples. {beta}-catenin nuclear localization and APC mutation were validated from serial FFPE sections representing same tumor regions. Several factors including status of KRAS mutation could not explain the absence of {beta}-catenin nuclear localization in tumor samples harboring APC mutation. This lack of correlation was validated in CRC cell lines harboring various APC mutations. Our results provide evidence directly from tumor samples for possible non-canonical role(s) for mutant APC.