Clinicopathologic characteristics of FBXW7-mutated colorectal adenocarcinoma and association with aberrant beta-catenin localization

David Escobar, Omar Bushara, Leyu Sun, Jie Liao, Guang Yu Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Oncogenic mutations in the adenomatous polyposis coli (APC)/Wnt signaling pathway are well documented. The FBXW7 gene (F-box and WD repeat domain–containing 7) encodes a member of the ubiquitin-proteasome complex that is more recently described to antagonize the oncogenic Wnt pathway by promoting the degradation of β-catenin encoded by the CTNNB1 gene. The pathologic significance of FBXW7 mutation in colorectal carcinoma (CRC) remains under-reported. In this study, we report the clinicopathologic and β-catenin immunohistochemical features of a single-institution cohort (83 cases) of FBXW7-mutated CRC compared with CTNNB1-mutated CRC. FBXW7-mutated CRC was more common in older patients (p = 0.031) and in the left/distal colon (p = 0.022). Immunohistochemical analysis revealed that aberrant nuclear/cytoplasmic β-catenin localization was identified in a significantly high proportion of FBXW7-mutated CRCs. When compared with CTNNB1-mutated CRC, FBXW7-mutated CRC showed a significantly higher proportion of microsatellite instability–stable tumors with intact expression of DNA mismatch repair proteins and had significantly more frequent co-occurrence of missense TP53 and KRAS mutations. The most frequently mutated FBXW7 residues/hotspots were located within the WD repeat domains (aa 378–659), which were also associated with aberrant nuclear/cytoplasmic localization of β-catenin protein. Our results indicate the unique pathologic characteristics of FBXW7-mutated CRC with frequent co-occurrence of missense mutant TP53 and KRAS. The mutated FBXW7 residues/hotspots and its association with aberrant nuclear/cytoplasmic β-catenin localization further support the oncogenic role of FBXW7 in colon carcinogenesis.

Original languageEnglish (US)
Pages (from-to)51-58
Number of pages8
JournalHuman pathology
Volume119
DOIs
StatePublished - Jan 2022

Keywords

  • APC
  • Colorectal carcinoma
  • CTNNB1
  • FBXW7
  • NGS
  • Wnt

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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