Epigenetic silencing of SMOC1 in traditional serrated adenoma and colorectal cancer

Colorectal sessile serrated adenoma/polyps (SSA/Ps) are well-known precursors of colorectal cancer (CRC) characterized by mutation and microsatellite instability. By contrast, the molecular characteristics of traditional serrated adenoma (TSAs) are not fully understood. We analyzed genome-wide DNA methylation in TSAs having both protruding and flat components. We identified 11 genes, including , methylation of which progressively increased during the development of TSAs. was prevalently methylated in TSAs, but was rarely methylated in SSA/Ps ( < 0.001). RT-PCR and immunohistochemistry revealed that SMOC1 was expressed in normal colon and SSA/Ps, but its expression was decreased in TSAs. Ectopic expression of SMOC1 suppressed proliferation, colony formation and tumor formation by CRC cells. Analysis of colorectal lesions ( = 847) revealed that is frequently methylated in TSAs, high-grade adenomas and CRCs. Among these, methylation was strongly associated with mutation and CpG island methylator phenotype (CIMP)-low. These results demonstrate that epigenetic silencing of is associated with TSA development but is rarely observed in SSA/Ps. SMOC1 expression could thus be a diagnostic marker of serrated lesions, and methylation could play a role in neoplastic pathways in TSAs and conventional adenomas.