BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis
- University of Michigan, United States
- Hiroshima University, Japan
- University of Utah Medical Schoo, United States
Abstract
While 20-30% of colorectal cancers (CRCs) may arise from precursors with serrated glands, only 8-10% of CRCs manifest serrated morphology at diagnosis. Markers for distinguishing CRCs arising from 'serrated' versus 'conventional adenoma' precursors are lacking. We studied 36 human serrated CRCs and found CDX2 loss or BRAF mutations in ~60% of cases and often together (p= .04). CDX2Null/BRAFV600E expression in adult mouse intestinal epithelium led to serrated morphology tumors (including carcinomas) and BRAFV600E potently interacted with CDX2 silencing to alter gene expression. Like human serrated lesions, CDX2Null/BRAFV600E-mutant epithelium expressed gastric markers. Organoids from CDX2Null/BRAFV600E-mutant colon epithelium showed serrated features, and partially recapitulated the gene expression pattern in mouse colon tissues. We present a novel mouse tumor model based on signature defects seen in many human serrated CRCs - CDX2 loss and BRAFV600E. The mouse intestinal tumors show significant phenotypic similarities to human serrated CRCs and inform about serrated CRC pathogenesis.
Data availability
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Colon tumor samples from mice with Braf V600E, Cdx2-/-, or both, as well as control colon, and tumors from Apc-/- mice.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE84650).
Article and author information
Author details
Funding
National Institutes of Health (R01CA082223)
- Eric R Fearon
National Institutes of Health (R01CA176839)
- Martin McMahon
National Institutes of Health (P30CA046592)
- Eric R Fearon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Procedures involving mice for the research described herein have been approved by the University of Michigan's Institutional Animal Care and Use Committee (PRO00005075) and were carried out according to Michigan state and US federal regulations.
Human subjects: The colorectal cancers were studied in accordance with the Ethical Guidelines for Human Genome/Gene Research enacted by the Japanese Government. We also studied human benign serrated colorectal lesions obtained from the University of Michigan tissue procurement service through an Institutional Review Board-approved protocol (#00058054).
Copyright
© 2017, Sakamoto et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis
eLife 6:e20331.
https://doi.org/10.7554/eLife.20331
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