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Elife. 2017 Jan 10;6. pii: e20331. doi: 10.7554/eLife.20331.

BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis.

Author information

1
Department of Internal Medicine, University of Michigan, Ann Arbor, United States.
2
Department of Molecular Pathology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
3
Department of Dermatology, University of Utah Medical School, Salt Lake City, United States.
4
Huntsman Cancer Institute, University of Utah Medical School, Salt Lake City, United States.
5
Department of Surgery, University of Michigan, Ann Arbor, United States.
6
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States.
7
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
8
Department of Pathology, University of Michigan, Ann Arbor, United States.
9
Department of Biostatistics, University of Michigan, Ann Arbor, United States.
10
Department of Human Genetics, University of Michigan, Ann Arbor, 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=0.04). 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.

KEYWORDS:

cancer biology; cancer diagnosis; colorectal cancer; homeobox gene; human; human biology; intestinal differentiation; medicine; mouse; oncogene; tumor suppressor gene

PMID:
28072391
PMCID:
PMC5268782
DOI:
10.7554/eLife.20331
[Indexed for MEDLINE]
Free PMC Article

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