Sa1986 Clinicopathologic Characteristics and Molecular Associations of Wnt/β-Catenin Signal in the Serrated Neoplasia Pathway of the Colorectum

Abstract

Background: Sessile serrated adenoma/polyp (SSA/P) is considered as an early precursor in the serrated neoplasia pathway leading to colorectal cancer with high levels of microsatellite instability. Recent studies have shown associations of SSA/P with predominance of proximal colon, MLH1 methylation, a CpG island methylator phenotype, and BRAF mutations. However, clinicopathlogical features of SSA/P with dysplasia or carcinoma remain unclear, and potential roles ofWNT/β-catenin signaling in serrated lesions are still controversial.Materials and methods: The materials for our study were 144 colorectal lesions, including 29 SSA/ Ps, 22 SSA/Ps with high-grade dysplasia and 13 SSA/Ps with submucosal carcinoma, as well as 29 conventional adenomas, 26 adenomas with high-grade dysplasia and 25 adenomas with submucosal carcinoma.We studied clinicopathological features of each group, including patient age, sex, location, macroscopic type, and tumor size, and performed β-catenin immunostaining, methylation specific PCR for MLH1 and WNT signaling associated genes such as AXIN2, APC,MCC and secreted frizzled-related proteins (SFRPs), and direct sequencing of BRAF/KRAS in all cases. Results: There was no difference in the age and sex distribution across each group of patients. SSA/P series were significantly located in the proximal colon compared with adenoma series (P < 0.001). SSA/P with high-garde dysplasia and submucosal carcinoma were significantly smaller in size than the corresponding adenoma counterparts. Immunohistochemically, nuclear β-catenin labelings were significantly lower in the serrated series than in their adenoma counterparts, and a significant increment in those labelings was found from SSA/P to SSA/P with high-grade dysplasia or submucosal carcinoma. In addition, their labelings were most prominent in the lower crypt zone in all SSA/P categories. The frequency of MLH1 methylation was significantly higher in SSA/P series, as compared to corresponding adenoma series. Similar trends were found in the frequency of SFRP4 methylation. AXIN2 and MCC were more frequently methylated in SSA/P with high-grade dysplasia and SSA/P with submucosal carcinoma than in adenoma counterparts. Stepwise increment of AXIN2 and MCC methylation was identified from SSA/P through SSA/P with high-grade dysplasia to SSA/P with submucosal carcinoma. Interestingly, a significant correlation was seen between nuclear β-catenin expression and methylation of AXIN2 or MCC in the SSA/P series (P < 0.001, respectively). BRAF mutation was more frequent, while KRAS mutation was less frequent in the SSA/P series as compared to the adenoma series. Conclusions: The serrated neoplasia pathway showed distinct clinicopathologic features, a high frequency of MLH1 methylation, and different WNT/β-catenin signal activation patterns, compared to conventional adenoma-carcinoma sequence.