Beta-catenin Nuclear Labeling is a Common Feature of Sessile Serrated Adenomas and Correlates With Early Neoplastic Progression After BRAF Activation

Recent observations indicate that some sessile serrated adenomas (SSAs) have aberrant beta-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 beta-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 beta-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 beta-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 beta-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 BRA F 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 Writ signaling pathway in SSAs, and further indicate that Writ pathway activation plays a role in the neoplastic progression of SSAs and TSAs to colonic carcinoma by mechanisms independent of CTNNB1 mutation.