Epigenetic silencing of SMOC1 in traditional serrated adenoma and colorectal cancer

// Hironori Aoki 1, * , Eiichiro Yamamoto 1, 2, * , Akira Takasawa 3 , Takeshi Niinuma 1 , Hiro-O Yamano 2 , Taku Harada 1 , Hiro-O Matsushita 4 , Kenjiro Yoshikawa 4 , Ryo Takagi 4 , Eiji Harada 4 , Yoshihito Tanaka 4 , Yuko Yoshida 4 , Tomoyuki Aoyama 3 , Makoto Eizuka 5 , Akira Yorozu 1 , Hiroshi Kitajima 1 , Masahiro Kai 1 , Norimasa Sawada 3 , Tamotsu Sugai 5 , Hiroshi Nakase 2 and Hiromu Suzuki 1 1 Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan 2 Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan 3 Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan 4 Department of Digestive Disease Center, Akita Red Cross Hospital, Akita, Japan 5 Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan * These authors contributed equally to this work Correspondence to: Hiromu Suzuki, email: hsuzuki@sapmed.ac.jp Keywords: SMOC1; colorectal cancer; traditional serrated adenoma; DNA methylation; CIMP Received: June 26, 2017      Accepted: November 30, 2017      Published: December 20, 2017 ABSTRACT Colorectal sessile serrated adenoma/polyps (SSA/Ps) are well-known precursors of colorectal cancer (CRC) characterized by BRAF 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 SMOC1 , methylation of which progressively increased during the development of TSAs. SMOC1 was prevalently methylated in TSAs, but was rarely methylated in SSA/Ps ( p < 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 in vivo tumor formation by CRC cells. Analysis of colorectal lesions ( n = 847) revealed that SMOC1 is frequently methylated in TSAs, high-grade adenomas and CRCs. Among these, SMOC1 methylation was strongly associated with KRAS mutation and CpG island methylator phenotype (CIMP)-low. These results demonstrate that epigenetic silencing of SMOC1 is associated with TSA development but is rarely observed in SSA/Ps. SMOC1 expression could thus be a diagnostic marker of serrated lesions, and SMOC1 methylation could play a role in neoplastic pathways in TSAs and conventional adenomas.