Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal 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 si...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2018-01-01
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| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2017.1411446 |
| _version_ | 1797678903411605504 |
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| author | Catherine E. Bond Cheng Liu Futoshi Kawamata Diane M. McKeone Winnie Fernando Saara Jamieson Sally-Ann Pearson Alexandra Kane Susan L. Woods Tamsin R. M. Lannagan Roshini Somashekar Young Lee Troy Dumenil Gunter Hartel Kevin J. Spring Jennifer Borowsky Lochlan Fennell Mark Bettington Jason Lee Daniel L. Worthley Barbara A. Leggett Vicki L. J. Whitehall |
| author_facet | Catherine E. Bond Cheng Liu Futoshi Kawamata Diane M. McKeone Winnie Fernando Saara Jamieson Sally-Ann Pearson Alexandra Kane Susan L. Woods Tamsin R. M. Lannagan Roshini Somashekar Young Lee Troy Dumenil Gunter Hartel Kevin J. Spring Jennifer Borowsky Lochlan Fennell Mark Bettington Jason Lee Daniel L. Worthley Barbara A. Leggett Vicki L. J. Whitehall |
| author_sort | Catherine E. Bond |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T23:06:42Z |
| format | Article |
| id | doaj.art-a0eb35f1f5c1498b9b8dd60644c1c526 |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:06:42Z |
| publishDate | 2018-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-a0eb35f1f5c1498b9b8dd60644c1c5262023-09-21T13:09:20ZengTaylor & Francis GroupEpigenetics1559-22941559-23082018-01-01131404810.1080/15592294.2017.14114461411446Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasiaCatherine E. Bond0Cheng Liu1Futoshi Kawamata2Diane M. McKeone3Winnie Fernando4Saara Jamieson5Sally-Ann Pearson6Alexandra Kane7Susan L. Woods8Tamsin R. M. Lannagan9Roshini Somashekar10Young Lee11Troy Dumenil12Gunter Hartel13Kevin J. Spring14Jennifer Borowsky15Lochlan Fennell16Mark Bettington17Jason Lee18Daniel L. Worthley19Barbara A. Leggett20Vicki L. J. Whitehall21QIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteThe University of Western SydneyThe University of Western SydneyThe University of Western SydneyThe University of Western SydneyQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteThe University of Western SydneyQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteSouth Australia Health and Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteColorectal 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.http://dx.doi.org/10.1080/15592294.2017.1411446brafcancer biologycolorectal cancerdna methylationmethylationmurine modelserrated neoplasia |
| spellingShingle | Catherine E. Bond Cheng Liu Futoshi Kawamata Diane M. McKeone Winnie Fernando Saara Jamieson Sally-Ann Pearson Alexandra Kane Susan L. Woods Tamsin R. M. Lannagan Roshini Somashekar Young Lee Troy Dumenil Gunter Hartel Kevin J. Spring Jennifer Borowsky Lochlan Fennell Mark Bettington Jason Lee Daniel L. Worthley Barbara A. Leggett Vicki L. J. Whitehall Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia Epigenetics braf cancer biology colorectal cancer dna methylation methylation murine model serrated neoplasia |
| title | Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia |
| title_full | Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia |
| title_fullStr | Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia |
| title_full_unstemmed | Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia |
| title_short | Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia |
| title_sort | oncogenic braf mutation induces dna methylation changes in a murine model for human serrated colorectal neoplasia |
| topic | braf cancer biology colorectal cancer dna methylation methylation murine model serrated neoplasia |
| url | http://dx.doi.org/10.1080/15592294.2017.1411446 |
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