To β or Not to β: Lack of Correlation Between APC Mutation and β-Catenin Nuclear Localization in Colorectal Cancer

Document Type

Article

Publication Title

Journal of Gastrointestinal Cancer

Abstract

Purpose: 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 β-catenin, resulting in transcriptional activation of cancer-promoting genes. Methods: β-catenin nuclear localization and APC mutation were validated from serial FFPE sections representing the same tumor regions, using immunohistochemistry and Sanger sequencing, respectively. Results: Here, we provide evidence for a surprising lack of correlation between APC mutation and β-catenin nuclear localization in early-onset sporadic rectal cancer samples. Several factors including status of KRAS mutation could not explain this anomaly. The lack of correlation was validated in CRC cell lines harboring various APC mutations. Conclusion: Our results provide evidence directly from tumor samples for possible non-canonical role(s) for mutant APC.

DOI

10.1007/s12029-022-00886-0

Publication Date

1-1-2022

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