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

Hum Pathol. 2022 Jan:119:51-58. doi: 10.1016/j.humpath.2021.10.003. Epub 2021 Oct 27.


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.

Keywords: APC; CTNNB1; Colorectal carcinoma; FBXW7; NGS; Wnt.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / chemistry*
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor* / analysis
  • Biomarkers, Tumor* / genetics
  • Colorectal Neoplasms / chemistry*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA Mutational Analysis
  • Databases, Factual
  • F-Box-WD Repeat-Containing Protein 7 / genetics*
  • Female
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunohistochemistry
  • Male
  • Microsatellite Instability
  • Middle Aged
  • Mutation*
  • Phenotype
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Tumor Suppressor Protein p53 / genetics
  • beta Catenin / analysis*
  • beta Catenin / genetics


  • Biomarkers, Tumor
  • CTNNB1 protein, human
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • KRAS protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • beta Catenin
  • Proto-Oncogene Proteins p21(ras)