Assessment of epigenetic alterations in early colorectal lesions containing BRAF mutations
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Takeshi Sawada1,2,*, Eiichiro Yamamoto1,3,*, Hiro-o Yamano4,*, Masanori Nojima5, Taku Harada1, Reo Maruyama1, Masami Ashida1, Hironori Aoki1, Hiro-o Matsushita4, Kenjiro Yoshikawa4, Eiji Harada4, Yoshihito Tanaka4, Shigenori Wakita6, Takeshi Niinuma1, Masahiro Kai1, Makoto Eizuka7, Tamotsu Sugai7, Hiromu Suzuki1
1Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
2Department of Advanced Research in Community Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
3Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan
4Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan
5Center for Translational Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
6Division of Cardiovascular Medicine, Department of Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
7Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Morioka, Japan
*These authors have contributed equally to this work
Takeshi Sawada, e-mail: [email protected]
Keywords: colorectal cancer, BRAF, serrated lesion, methylation, CpG island methylator phenotype
Received: December 11, 2015 Accepted: April 11, 2016 Published: April 27, 2016
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.
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