BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis.

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.

• Authors: Naoya Sakamoto, Ying Feng, Carmine Stolfi, Yuki Kurosu, Maranne Green, Jeffry Lin, Megan E Green, Kazuhiro Sentani, Wataru Yasui, Martin McMahon, Karin M Hardiman, Jason R Spence, Nobukatsu Horita, Joel K Greenson, Rork Kuick, Kathleen R Cho, Eric R Fearon
• Journal: eLife (Elife) Vol. 6 (01 10 2017) ISSN: 2050-084X [Electronic] England
• PMID: 28072391 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CDX2 Transcription Factor
• CDX2 protein, human
• Cdx2 protein, mouse
• BRAF protein, human
• Braf protein, mouse
• Proto-Oncogene Proteins B-raf

Topics

• Animals
• CDX2 Transcription Factor (genetics, metabolism)
• Carcinogenesis
• Colon (pathology)
• Colorectal Neoplasms (pathology, physiopathology)
• Disease Models, Animal
• Gene Expression Profiling
• Intestinal Mucosa (pathology)
• Mice
• Organoids
• Proto-Oncogene Proteins B-raf (genetics, metabolism)