Journal article
Attenuation of the CpG island methylator phenotype and lack of WNT signalling activation restrains Kras mutant intestinal neoplasia
BJC, Vol.Advanced access
23-Feb-2026
PMID: 41731118
Abstract
Background
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.
Methods
Temporospatial activation of oncogenic BrafV637 or KrasG12D was induced in murine intestine. Differential expression, methylation and pathways analyses identified oncogene-specific alterations.
Results
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.
Conclusion
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.
Details
- Title
- Attenuation of the CpG island methylator phenotype and lack of WNT signalling activation restrains Kras mutant intestinal neoplasia
- Authors
- Lochlan Fennell (Corresponding Author) - University of the Sunshine Coast, Queensland, School of Health - BiomedicineCheng Liu - QIMR Berghofer Medical Research InstituteAlexandra Kane - The University of QueenslandSimon Tria - QIMR Berghofer Medical Research InstituteJennifer Borowsky - The University of QueenslandLu Chai - Monash UniversitySarron Randall-Demllo - Monash UniversityDiane McKeone - QIMR Berghofer Medical Research InstituteCatherine Bond - The University of QueenslandBarbara Leggett - The University of QueenslandVicki Whitehall - The University of Queensland
- Publication details
- BJC, Vol.Advanced access
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/s41416-025-03271-3
- ISSN
- 1532-1827
- PMID
- 41731118
- Copyright note
- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Data Availability
- The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.
- Organisation Unit
- School of Health - Biomedicine; Cancer Research Cluster
- Language
- English
- Record Identifier
- 991210074402621
- Output Type
- Journal article
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