Attenuation of the CpG island methylator phenotype and lack of WNT signalling activation restrains Kras mutant intestinal neoplasia.

Serrated neoplasia arises from serrated precursor lesions. Hyperplastic polyps commonly activate MAPK signalling, initiated by BRAF or KRAS mutation, but premalignant KRAS-mutant sessile serrated lesions are rare. Here, we model Kras- and Braf-mutant neoplasia in vivo comparing histological, transcriptomic, and epigenetic changes. Temporospatial activation of oncogenic BrafV637 or KrasG12D was induced in murine intestine. Differential expression, methylation and pathways analyses identified oncogene-specific alterations. Prolonged exposure to oncogenic Braf is associated with a time-dependent accumulation of murine serrated precursors (mSP, P = 3 × 10-10), and murine serrated lesions (mSL) and invasive cancer (8 × 10-8). Kras-mutants acquired fewer mSPs (P = 0.06) and lower probability of developing mSLs (P = 0.004). Kras-mutant mSLs rarely develop aberrant WNT signalling (1/23). Transcriptomic profiles diverged, with Braf-mutant intestines showing enriched immune and inflammatory signalling. Deconvolution analysis revealed Braf-mutants had comparably higher macrophage infiltrate (P = 0.025) and upregulation of M1 macrophage gene sets (P = 0.0008). Both mutations showed accumulating DNA methylation, however, an attenuated rate in a subset of CpG sites (1306) was observed in Kras-mutant intestine. Kras mutation can induce serrated neoplasia, but with significantly greater latency period and lower penetrance compared to Braf. Kras-mutant neoplasms display an attenuated CIMP-like phenotype, rarely developing aberrant WNT signalling. These data refine our understanding of MAPK-induced intestinal neoplasia.