APC Mutation marks an aggressive subtype of BRAF mutant colorectal cancers

Background & AimsWNT activation is a hallmark of colorectal cancer. BRAF mutation is present in 15% of colorectal cancers, and the role of mutations in WNT signaling regulators in this context is unclear. Here we evaluate the mutational landscape of WNT signaling regulators in BRAF mutant cancers. MethodsWe performed exome-sequencing on 24 BRAF mutant colorectal cancers and analysed these data in combination with 175 publicly available BRAF mutant colorectal cancer exomes. We assessed the somatic mutational landscape of WNT signaling regulators, and performed hotspot and driver mutation analyses to identify potential drivers of WNT signaling. The effects of Apc and Braf mutation were modelled, in vivo, using the Apcmin/+ and BrafV637/Villin-CreERT2/+ mouse, respectively. ResultsRNF43 was the most frequently mutated WNT signaling regulator (41%). Mutations in the beta-catenin destruction complex occurred in 48% of cancers. Hotspot analyses identified potential cancer driver genes in the WNT signaling cascade, including MEN1, GNG12 and WNT16. Truncating APC mutation was identified in 20.8% of cancers. Truncating APC mutation was associated with early age at diagnosis (P< 2x10-5), advanced stage (P<0.01), and poor survival (P=0.026). Apcmin/+/BrafV637 animals had more numerous and larger SI and colonic lesions (P<0.0001 and P<0.05, respectively), and a markedly reduced survival (Median survival: 3.2 months, P=8.8x10-21) compared to animals with Apc or Braf mutation alone. ConclusionsThe WNT signaling axis is frequently mutated in BRAF mutant colorectal cancers. WNT16 and MEN1 may be novel drivers of aberrant WNT signaling in colorectal cancer. Co-mutation of BRAF and APC generates an extremely aggressive neoplastic phenotype that is associated with poor patient outcome. SynopsisWe have comprehensively evaluated the somatic mutation landscape of WNT signaling regulators in serrated colorectal cancers. We identified a mosaic of mutations that may be responsible for elevating WNT signaling in this context. Approximately 20% of serrated colorectal cancers harbor truncating APC mutation, and these cancers confer extremely poor prognoses.