Mucin phenotype and genetic alterations in non-V600E BRAF-mutated colorectal cancer

Hum Pathol. 2024 Mar:145:71-79. doi: 10.1016/j.humpath.2024.02.009. Epub 2024 Feb 27.

Abstract

Colorectal cancer (CRC) is a heterogeneous disease that develops through stepwise accumulation of genetic alterations and progresses via several distinct pathways. However, the tumorigenesis of CRCs with BRAF non-V600E mutations remains unclear. Here, we aimed to elucidate the tumorigenesis of CRCs with BRAF non-V600E mutations, focusing on differences in mucin phenotype and genetic alterations between CRCs with non-V600E and V600E mutations. We investigated 201 patients with CRC and performed panel testing of 415 genes to identify BRAF mutations. Patients were classified into five mucin phenotypes - large-intestinal, small-intestinal, gastric, mixed, and unclassified - using immunohistochemistry for CD10, MUC2, MUC5AC, and MUC6. BRAF mutations were identified in 24 of 201 patients' samples, of which 13 (6.5%) had a V600E mutation (V600E-mutant) and 11 (5.5%) had non-V600E mutations (non-V600E-mutant). MUC5AC expression was significantly associated with V600E mutations (P = 0.040), while CD10 expression was significantly associated with non-V600E mutations (P = 0.010). The small-intestinal mucin phenotype was significantly associated with non-V600E mutations (P = 0.031), while the mixed mucin phenotype was significantly associated with V600E mutations (P = 0.027). Regarding genetic alterations, focusing on the WNT signaling pathway, APC mutation was significantly associated with non-V600E mutations (P < 0.001), while RNF43 mutation was significantly associated with V600E mutations (P = 0.020). Considering the differences in mucin phenotype and genetic alterations, different modes of tumorigenesis are assumed for CRC with BRAF V600E mutation and non-V600E mutations. These findings are important in understanding the biology and treatment strategies for BRAF-mutant CRC.

Keywords: BRAF V600E; BRAF non-V600E; Colorectal cancer; Gene panel testing; Genetic alteration; Mucin phenotype.

MeSH terms

  • Carcinogenesis
  • Cell Transformation, Neoplastic
  • Colorectal Neoplasms* / genetics
  • Humans
  • Mutation
  • Phenotype
  • Proto-Oncogene Proteins B-raf* / genetics

Substances

  • Proto-Oncogene Proteins B-raf
  • BRAF protein, human