title: DNA methylation epigenotype and clinical features of NRAS-mutation(+) colorectal cancer.
abstract: Sporadic colorectal cancer (CRC) is classified into several molecular subtypes. We previously established two groups of DNA methylation markers through genome-wide DNA methylation analysis to classify CRC into distinct subgroups: high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME, respectively). HME CRC, also called CpG island methylator phenotype (CIMP)-high CRC, shows methylation of both Group 1 markers (CIMP markers) and Group 2 markers, while IME/CIMP-low CRC shows methylation of Group 2, but not of Group 1 markers, and LME CRC shows no methylation of either Group 1 or Group 2 markers. While BRAF- and KRAS-mutation(+) CRC strongly correlated with HME and IME, respectively, clinicopathological features of NRAS-mutation(+) CRC, including association with DNA methylation, remain unclear. To characterize NRAS-mutation(+) CRC, the methylation levels of 19 methylation marker genes (6 Group 1 and 13 Group 2) were analyzed in 61 NRAS-mutation(+) and 144 NRAS-mutation(-) CRC cases by pyrosequencing, and their correlation with clinicopathological features was investigated. Different from KRAS-mutation(+) CRC, NRAS-mutation(+) CRC significantly correlated with LME. NRAS-mutation(+) CRC showed significantly better prognosis than KRAS-mutation(+) CRC (P = 3 × 10-4). NRAS-mutation(+) CRC preferentially occurred in elder patients (P = 0.02) and at the distal colon (P = 0.006), showed significantly less lymph vessel invasion (P = 0.002), and correlated with LME (P = 8 × 10-5). DNA methylation significantly accumulated at the proximal colon. NRAS-mutation(+) CRC may constitute a different subgroup from KRAS-mutation(+) CRC, showing significant correlation with LME, older age, distal colon, and relatively better prognosis.
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.|Department of Digestive Surgery and Pathology, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Takane
authors.affiliation: Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan.
authors.forename: Kiwamu
authors.initials: K
authors.lastname: Akagi
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukuyo
authors.affiliation: Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Yagi
authors.affiliation: Department of Digestive Surgery and Pathology, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Takayama
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Atsushi
authors.identifier: http://orcid.org/0000-0002-6980-5515
authors.initials: A
authors.lastname: Kaneda
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D017422:Sequence Analysis, DNA; D016019:Survival Analysis
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BRAF mutation; DNA methylation; KRAS mutation; NRAS mutation; colorectal cancer