Up and downregulation of p16Ink4a expression in BRAF-mutated polyps/adenomas indicates a senescence barrier in the serrated route to colon cancer
Open accessAbstract
P16(Ink4a) is an important factor in carcinogenesis and its expression can be linked to oncogene-induced senescence. Oncogene-induced senescence is characterized by growth arrest and occurs as a consequence of oncogene activation due to KRAS or BRAF mutation. It has been shown that the induction of p16(Ink4a) in premalignant lesions and its loss during malignant transformation is an important mechanism in the carcinogenesis of several tumours. Loss of p16(Ink4a) is often caused by CDKN2A promoter hypermethylation. This mechanism of gene silencing is associated with the CpG island methylator phenotype (CIMP) in colorectal carcinomas, which is characterized by widespread promoter methylation. In particular, colorectal carcinomas with BRAF mutations have been shown to be strongly associated with CIMP. Also, BRAF mutations are strongly correlated with the serrated route to colorectal cancer. In this study, we investigated p16(Ink4a) expression and promoter methylation in BRAF-mutated serrated lesions of the colon. P16(Ink4a) expression was found to be upregulated in premalignant lesions and was lost in invasive serrated carcinomas. P16(Ink4a) expression and Ki67 expression were mutually exclusive, indicating that p16(Ink4a) acts as cell cycle inhibitor. Additionally, progression of malignant transformation in serrated lesions was accompanied by increasing methylation of the CDKN2A promoter. Therefore, our data provide evidence for oncogene-induced senescence in the serrated route to colorectal cancer with BRAF mutation and upregulation of p16(Ink4a) expression appears to be a useful indicator of induction of senescence. Loss of p16(Ink4a) expression occurs during malignant transformation and is caused mainly by aberrant methylation of the CDKN2A promoter.
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Colon SSAs are mainly driven by activating BRAF mutations that trigger OIS.
“Colon SSAs are mainly driven by activating BRAF mutations that trigger OIS 31,34,35 .”
From A complex secretory program orchestrated by the inflammasome controls paracrine senescence (2013) · cites this paper as [34]
The Discussion (page unavailable) says that initiating BRAF mutations might drive oncogene-induced senescence in human serrated polyps, and concludes that the data provide evidence for senescence in the BRAF-mutated serrated route. It does not establish that colon sessile serrated adenomas are mainly driven by BRAF mutations: the study selected BRAF-mutated lesions for its final analysis, and its proposed causal link is hedged. (LLM, conf=0.85)
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- Authors
- Kriegl, L., Neumann, J., Vieth, M., Greten, F. R., Reu, S., Jung, A., & Kirchner, T.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- Bayreuth Medical Center (DE)
- TUM Klinikum (DE)
- Corresponding author
- Kriegl, Lydia
- Venue
- Modern Pathology
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 24
- Issue
- 7
- Pages
- 1015-1022
- ISSN
- 0893-3952 (ISSN-L)
- OpenAlex
- W2062854830
- Cited by
- 99
- References
- 5
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 9 · 2020: 5 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 7 · 2015: 9 · 2014: 12 · 2013: 12 · 2012: 8
- FWCI
- 7.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Modern Pathology (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- p16INK4a, BRAF mutation, colorectal cancer, oncogene-induced senescence, CpG island methylator phenotype, serrated adenoma, malignant transformation, Ki-67, cell cycle inhibition, precancerous lesions
- MeSH terms
- Adenoma, Adult, Aged, Aged, 80 and over, Cell Transformation, Neoplastic, Colonic Neoplasms, DNA Mutational Analysis, Humans, Immunohistochemistry, Middle Aged, Mutation, Precancerous Conditions, Promoter Regions, Genetic, Down-Regulation, Up-Regulation, Gene Expression Regulation, Neoplastic, Cellular Senescence, Adenomatous Polyps, DNA Methylation, Cyclin-Dependent Kinase Inhibitor p16, Genes, p16, Proto-Oncogene Proteins B-raf
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