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.
Highlights
Colorectal cancers (CRC) have accumulated defects in oncogenes and tumor suppressor genes (TSGs) (Fearon and Vogelstein, 1990)
We carried out analyses of selected molecular alterations in the 36 CRCs, focusing on the following: (i) DNA sequence-based determination of KRAS codons 12, 13, and 61 and BRAFT1799A(encoding BRAFV600E) missense mutations; (ii) DNA-based analyses of microsatellite instability-high (MSI-H) and CpG island methylation phenotype high-frequency (CIMP-H) status; (iii) immunohistochemical (IHC) studies of b-catenin, p53, MLH1, p16INK4A, and CDX2 to inform about the expression and functional status of selected TSG pathways and proteins; and (iv) IHC studies of annexin A10 (ANXA10) and MUC5AC to inform about aberrant gastric epithelial marker expression
One challenge in studying the pathogenesis of the CRCs that arise from serrated precursors is there are no known biomarkers that can definitively distinguish CRCs that arose from serrated lesions from CRCs arising from conventional adenomas (Bettington et al, 2013; Jass, 2007a; Langner, 2015)
Summary
Colorectal cancers (CRC) have accumulated defects in oncogenes and tumor suppressor genes (TSGs) (Fearon and Vogelstein, 1990). Serrated benign lesions arising in the colon and rectum include hyperplastic polyps (HPPs), sessile serrated adenomas/polyps (SSAs/SSPs), and traditional serrated adenomas (TSAs) (Bettington et al, 2013; Langner, 2015). Some SSAs/SSPs and TSAs, such as those showing dysplasia, have potential to progress to CRC (Bettington et al, 2013; Jass, 2007a; Langner, 2015). All three serrated benign lesion subtypes may have malignant potential, with SSAs and TSAs having higher potential than HPPs
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