Assessment of epigenetic alterations in early colorectal lesions containing BRAF mutations

// Takeshi Sawada 1, 2, * , Eiichiro Yamamoto 1, 3, * , Hiro-o Yamano 4, * , Masanori Nojima 5 , Taku Harada 1 , Reo Maruyama 1 , Masami Ashida 1 , Hironori Aoki 1 , Hiro-o Matsushita 4 , Kenjiro Yoshikawa 4 , Eiji Harada 4 , Yoshihito Tanaka 4 , Shigenori Wakita 6 , Takeshi Niinuma 1 , Masahiro Kai 1 , Makoto Eizuka 7 , Tamotsu Sugai 7 , Hiromu Suzuki 1 1 Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan 2 Department of Advanced Research in Community Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan 3 Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan 4 Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan 5 Center for Translational Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan 6 Division of Cardiovascular Medicine, Department of Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan 7 Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Morioka, Japan * These authors have contributed equally to this work Correspondence to: Takeshi Sawada, e-mail: tsawada@staff.kanazawa-u.ac.jp Keywords: colorectal cancer, BRAF, serrated lesion, methylation, CpG island methylator phenotype Received: December 11, 2015     Accepted: April 11, 2016     Published: April 27, 2016 ABSTRACT To clarify the molecular and clinicopathological characteristics of colorectal serrated lesions, we assessed the DNA methylation of cancer-associated genes in a cohort of BRAF -mutant precancerous lesions from 94 individuals. We then compared those results with the lesions’ clinicopathological features, especially colorectal subsites. The lesions included hyperplastic polyps (n = 16), traditional serrated adenomas (TSAs) (n = 15), TSAs with sessile serrated adenomas (SSAs) (n = 6), SSAs (n = 49) and SSAs with dysplasia (n = 16). The prevalence of lesions exhibiting the CpG island methylator phenotype (CIMP) was lower in the sigmoid colon and rectum than in other bowel subsites, including the cecum, ascending, transverse and descending colon. In addition, several cancer-associated genes showed higher methylation levels within lesions in the proximal to sigmoid colon than in the sigmoid colon and rectum. These results indicate that the methylation status of lesions with BRAF mutation is strongly associated with their location, histological findings and neoplastic pathways. By contrast, no difference in aberrant DNA methylation was observed in normal-appearing background colonic mucosa along the bowel subsites, which may indicate the absence of an epigenetic field defect.