title: Sporadic microsatellite instability-high colon cancers rarely display immunohistochemical evidence of Wnt signaling activation.
abstract: Most sporadic colonic adenocarcinomas are microsatellite stable (MSS) and arise from conventional adenomas by dysregulation of the APC/β-catenin/Wnt signaling pathway. Sporadic adenocarcinomas with a high degree of microsatellite instability (MSI) likely arise from sessile serrated polyps through the serrated neoplastic pathway. These polyps contain BRAF mutations and are prone to epigenetic methylation that ultimately silences MLH1, leading to MSI and heralding progression of dysplasia to invasive adenocarcinoma. Most investigators believe that these 2 models of cancer progression are mutually exclusive, although recent studies describe Wnt signaling activation in serrated polyps and propose that it plays a role in the development of sporadic colonic adenocarcinomas with MSI. We sought to test this hypothesis by evaluating β-catenin immunoexpression in 44 sporadic microsatellite unstable adenocarcinomas and 44 MSS colon cancers. We defined sporadic MSI-high carcinomas as those with loss of MLH1 and PMS2 immunostaining and BRAF V600E mutations that occurred in patients 50 years of age or older without a family history of colonic adenocarcinoma or Lynch syndrome. Forty-one (93%) of these carcinomas displayed membranous β-catenin staining only, compared with 28 (64%) site-matched MSS tumors with abnormal nuclear β-catenin staining.
authors.affiliation: *Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY †Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Panarelli
authors.forename: Cecily P
authors.initials: CP
authors.lastname: Vaughn
authors.forename: Wade S
authors.initials: WS
authors.lastname: Samowitz
authors.forename: Rhonda K
authors.initials: RK
authors.lastname: Yantiss
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D000230:Adenocarcinoma / Q000737:chemistry* / Q000235:genetics* / Q000473:pathology; D000251:Adenosine Triphosphatases / Q000032:analysis; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002462:Cell Membrane / Q000737:chemistry; D002467:Cell Nucleus / Q000737:chemistry; D003110:Colonic Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D060885:Multiplex Polymerase Chain Reaction; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000032:analysis; D011237:Predictive Value of Tests; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012189:Retrospective Studies; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000032:analysis*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D051176:beta Catenin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes