Up and downregulation of p16Ink4a expression in BRAF-mutated polyps/adenomas indicates a senescence barrier in the serrated route to colon cancer View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2011-07

AUTHORS

Lydia Kriegl, Jens Neumann, Michael Vieth, Florian R Greten, Simone Reu, Andreas Jung, Thomas Kirchner

ABSTRACT

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. More... »

PAGES

1015

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/modpathol.2011.43

DOI

http://dx.doi.org/10.1038/modpathol.2011.43

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1033923407

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21423154


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