BRAF^V600E 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 <i>BRAF</i> mutations in ~60% of cases and often together (p<i>=</i>0.04). CDX2^Null/BRAF^V600E expression in adult mouse intestinal epithelium led to serrated morphology tumors (including carcinomas) and BRAF^V600E potently interacted with CDX2 silencing to alter gene expression. Like human serrated lesions, CDX2^Null/BRAF^V600E-mutant epithelium expressed gastric markers. Organoids from CDX2^Null/BRAF^V600E-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 BRAF^V600E. The mouse intestinal tumors show significant phenotypic similarities to human serrated CRCs and inform about serrated CRC pathogenesis.