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

TL;DR

This study compares how Kras and Braf mutations affect intestinal cancer development, finding that Kras mutations lead to slower, less aggressive cancer growth.

Contribution

The study reveals that Kras-mutant intestinal neoplasia has a delayed onset, lower cancer progression, and reduced WNT signaling activation compared to Braf mutations.

Findings

Kras-mutant mice develop fewer serrated precursor lesions and have a lower chance of progressing to invasive cancer.

Kras-mutant tumors rarely show WNT signaling activation and exhibit a reduced CpG island methylator phenotype.

Braf-mutant tumors show increased immune cell infiltration and inflammatory signaling compared to Kras-mutant tumors.

Abstract

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.

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