Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia

Catherine Bond; Cheng Liu; Futoshi Kawamata; Diane McKeone; Winnie Fernando; Saara Jamieson; Sally-Anne Pearson; Alexandra Kane; Susan L Woods; Tamsin R Lannagan; Roshini Somashekar; Young Lee; Troy Dumenil; Gunter Hartel; Kevin J Spring; Jennifer Borowsky; Lochlan Fennell; Mark Bettington; Jason Lee; Daniel L Worthley; Barbara Leggett; Vicki Whitehall

doi:10.1080/15592294.2017.1411446

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Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia

Journal article

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Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia

Catherine Bond, Cheng Liu, Futoshi Kawamata, Diane McKeone, Winnie Fernando, Saara Jamieson, Sally-Anne Pearson, Alexandra Kane, Susan L Woods, Tamsin R Lannagan, …

Epigenetics, Vol.13(1), pp.40-48

2018

DOI: https://doi.org/10.1080/15592294.2017.1411446

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Abstract

Biochemistry and Cell Biology

Medical Biochemistry and Metabolomics

BRAF

DNA methylation

cancer biology

colorectal cancer

methylation

murine model

serrated neoplasia

Colorectal cancer is a major cause of cancer death and approximately 20% arises within serrated polyps, which are under-recognized and poorly understood. Human serrated colorectal polyps frequently exhibit both oncogenic BRAF mutation and widespread DNA methylation changes, which are important in silencing genes restraining neoplastic progression. Here, we investigated whether in vivo induction of mutant Braf is sufficient to result in coordinated promoter methylation changes for multiple cancer-related genes. The BrafV637E mutation was induced in murine intestine on an FVB;C57BL/6J background and assessed for morphological and DNA methylation changes at multiple time points from 10 days to 14 months. Extensive intestinal hyperplasia developed by 10 days post-induction of the mutation. By 8 months, most mice had murine serrated adenomas with dysplasia and invasive cancer developed in 40% of mice by 14 months. From 5 months onwards, Braf mutant mice showed extensive, gene-specific increases in DNA methylation even in hyperplastic mucosa without lesions. This demonstrates that persistent oncogenic Braf signaling is sufficient to induce widespread DNA methylation changes. This occurs over an extended period of time, mimicking the long latency followed by rapid progression of human serrated neoplasia. This study establishes for the first time that DNA methylation arises slowly in direct response to prolonged oncogenic Braf signaling in serrated polyps; this finding has implications both for chemoprevention and for understanding the origin of DNA hypermethylation in cancer generally.

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Title: Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia
Authors: Catherine Bond (Author) - Queensland Medical Institute of Research
Cheng Liu (Author) - Queensland Medical Institute of Research
Futoshi Kawamata (Author) - Queensland Medical Institute of Research
Diane McKeone (Author) - Queensland Medical Institute of Research
Winnie Fernando (Author) - Queensland Medical Institute of Research
Saara Jamieson (Author) - Queensland Medical Institute of Research
Sally-Anne Pearson (Author) - Queensland Medical Institute of Research
Alexandra Kane (Author) - Queensland Medical Institute of Research
Susan L Woods (Author) - University of Western Sydney
Tamsin R Lannagan (Author) - University of Western Sydney
Roshini Somashekar (Author) - University of Western Sydney
Young Lee (Author) - University of Western Sydney
Troy Dumenil (Author) - Queensland Medical Institute of Research
Gunter Hartel (Author) - Queensland Medical Institute of Research
Kevin J Spring (Author) - University of Western Sydney
Jennifer Borowsky (Author) - Queensland Medical Institute of Research
Lochlan Fennell (Author) - Queensland Medical Institute of Research
Mark Bettington (Author) - Queensland Medical Institute of Research
Jason Lee (Author) - Queensland Medical Institute of Research
Daniel L Worthley (Author) - University of Adelaide
Barbara Leggett (Author) - Queensland Medical Institute of Research
Vicki Whitehall (Author) - Queensland Medical Institute of Research
Publication details: Epigenetics, Vol.13(1), pp.40-48
Publisher: Taylor & Francis Inc.
Date published: 2018
DOI: 10.1080/15592294.2017.1411446
ISSN: 1559-2294
Copyright note: Copyright © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
Organisation Unit: School of Health - Biomedicine; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99450460202621
Output Type: Journal article

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Web Of Science research areas: Biochemistry & Molecular Biology; Genetics & Heredity

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