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

<h4>Background</h4>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.<h4>Methods</h4>Temporospatial activation of oncogenic Braf^V637 or Kras^G12D was induced in murine intestine. Differential expression, methylation and pathways analyses identified oncogene-specific alterations.<h4>Results</h4>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.<h4>Conclusion</h4>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.