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Published VersionCC BY-NC V4.0, Open Access
Journal article
Braf mutation induces rapid neoplastic transformation in the aged and aberrantly methylated intestinal epithelium
Gut, Vol.71(6), pp.1127-1140
2022
PMID: 34230216
Abstract
Objective
Sessile serrated lesions (SSLs) are common across the age spectrum, but the BRAF mutant cancers arising occur predominantly in the elderly. Aberrant DNA methylation is uncommon in SSL from young patients. Here, we interrogate the role of ageing and DNA methylation in SSL initiation and progression.
Design
We used an inducible model of Braf mutation to direct recombination of the oncogenic Braf V637E allele to the murine intestine. BRAF mutation was activated after periods of ageing, and tissue was assessed for histological, DNA methylation and gene expression changes thereafter. We also investigated DNA methylation alterations in human SSLs.
Results
Inducing Braf mutation in aged mice was associated with a 10-fold relative risk of serrated lesions compared with young mice. There were extensive differences in age-associated DNA methylation between animals induced at 9 months versus wean, with relatively little differential Braf-specific methylation. DNA methylation at WNT pathway genes scales with age and Braf mutation accelerated age-associated DNA methylation. In human SSLs, increased epigenetic age was associated with high-risk serrated colorectal neoplasia.
Conclusions
SSLs arising in the aged intestine are at a significantly higher risk of spontaneous neoplastic progression. These findings provide support for a new conceptual model for serrated colorectal carcinogenesis, whereby risk of Braf-induced neoplastic transformation is dependent on age and may be related to age-associated molecular alterations that accumulate in the ageing intestine, including DNA methylation. This may have implications for surveillance and chemopreventive strategies targeting the epigenome.
Details
- Title
- Braf mutation induces rapid neoplastic transformation in the aged and aberrantly methylated intestinal epithelium
- Authors
- Lochlan Fennell (Corresponding Author) - The University of QueenslandAlexandra Kane - Conjoint Internal Medical Laboratory, Chemical Pathology, Health Support Queensland Pathology Queensland, Herston, Queensland, AustraliaCheng Liu - Faculty of Medicine, The University of Queensland, Saint Lucia, Queensland, AustraliaDiane McKeone - The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, AustraliaGunter Hartel - QIMR Berghofer Medical Research InstituteChang Su - The University of QueenslandCatherine Bond - Faculty of Medicine, The University of Queensland, Saint Lucia, Queensland, AustraliaMark Bettington - Envoi Specialist Pathologists, Brisbane, Queensland, AustraliaBarbara Leggett - Royal Brisbane and Women's HospitalVicki Whitehall - QIMR Berghofer Medical Research Institute
- Publication details
- Gut, Vol.71(6), pp.1127-1140
- Publisher
- BMJ Group
- Date published
- 2022
- DOI
- 10.1136/gutjnl-2020-322166
- ISSN
- 1468-3288; 0017-5749
- PMID
- 34230216
- Copyright note
- © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
- Data Availability
- Data are available on reasonable request.
- Organisation Unit
- School of Health - Biomedicine; Cancer Research Cluster
- Language
- English
- Record Identifier
- 991020698902621
- Output Type
- Journal article
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