Beta-catenin Nuclear Labeling is a Common Feature of Sessile Serrated Adenomas and Correlates With Early Neoplastic Progression After BRAF Activation
- 1 December 2009
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in The American Journal of Surgical Pathology
- Vol. 33 (12), 1823-1832
- https://doi.org/10.1097/pas.0b013e3181b6da19
Abstract
Recent observations indicate that some sessile serrated adenomas (SSAs) have aberrant β-catenin nuclear labeling, implicating the Wnt pathway in the molecular progression of SSAs to colorectal carcinoma. We sought to expand upon this finding by characterizing β-catenin expression in the full spectrum of serrated colorectal polyps, and correlating these findings with the genetic status of BRAF, KRAS and CTNNB1. Immunolabeling for β-catenin confirmed the presence of abnormal nuclear accumulation in SSAs, with 35/54 (67%) SSAs showing nuclear labeling compared with 0/12 hyperplastic polyps. Abnormal nuclear labeling was also identified in 4/11 (36%) traditional serrated adenomas (TSAs) (P=0.00001). When SSAs were further analyzed with respect to the presence or absence of conventional epithelial dysplasia, nuclear β-catenin labeling was seen in 8/27 (29%) SSAs without dysplasia (SSA) but in 27/27 (100%) of SSAs with dysplasia (P=0.000001). Sequencing of genomic DNA extracted from a subset of hyperplastic polyps, SSAs, SSAs with dysplasia, TSAs and tubular adenomas failed to identify any CTNNB1 mutations to account for abnormal β-catenin nuclear labeling. However, abnormal nuclear labeling always occurred in the setting of a BRAF V600E mutation, indicating aberrant nuclear labeling occurs on a background of BRAF activation. Of interest, all 6 TSAs contained a KRAS mutation confirming that SSAs and TSAs are genetically distinct entities. These findings validate previous reports implicating activation of the Wnt signaling pathway in SSAs, and further indicate that Wnt pathway activation plays a role in the neoplastic progression of SSAs and TSAs to colonic carcinoma by mechanisms independent of CTNNB1 mutation.Keywords
This publication has 31 references indexed in Scilit:
- Distinct CpG island methylation profiles and BRAF mutation status in serrated and adenomatous colorectal polypsInternational Journal of Cancer, 2008
- Frequent β-Catenin Nuclear Labeling in Sessile Serrated Polyps of the Colorectum With Neoplastic PotentialAmerican Journal of Clinical Pathology, 2008
- Sessile serrated polyps of the colorectum are rare in patients with Lynch syndrome and in familial colorectal cancer familiesFamilial Cancer, 2007
- Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a ‘fusion’ pathway to colorectal cancerHistopathology, 2006
- CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancerNature Genetics, 2006
- Small Colonic Microsatellite Unstable Adenocarcinomas and High-Grade Epithelial Dysplasias in Sessile Serrated Adenoma Polypectomy SpecimensAmerican Journal of Clinical Pathology, 2006
- Proximal versus distal hyperplastic polyps of the colorectum: different lesions or a biological spectrum?Journal of Clinical Pathology, 2004
- Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancerNature Genetics, 2004
- Mutations of the APC(Adenomatous Polyposis Coli) Gene in FAP(Familial Polyposis Coli) Patients and in Sporadic Colorectal Tumors.The Tohoku Journal of Experimental Medicine, 1992
- Genetic Alterations during Colorectal-Tumor DevelopmentThe New England Journal of Medicine, 1988