DNA methylation epigenotype and clinical features of NRAS‐mutation(+) colorectal cancer. (4th April 2017)

• Record Type: Journal Article
• Authors: Takane, Kiyoko; Akagi, Kiwamu; Fukuyo, Masaki; Yagi, Koichi; Takayama, Tadatoshi; Kaneda, Atsushi
• Is Part Of: Cancer medicine. Volume 6:Number 5(2017:May)
• Page Start: 1023
• Page End: 1035
• Publication Date: 2017-04-04
• Subjects: BRAF mutation -- colorectal cancer -- DNA methylation -- KRAS mutation -- NRAS mutation; 616.994005
• DOI: 10.1002/cam4.1061
• Languages: English
• ISSNs: 2045-7634

Abstract

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. Abstract : Genetic and epigenetic analyses of colorectal cancer (CRC) were conducted to clarify molecular and clinicopathological features of NRAS ‐mutation(+) CRC compared to KRAS ‐mutation(+) and other subgroups of CRC. NRAS ‐mutation(+) CRC presented a low‐methylation epigenotype, occurred in elder patients and at the distal colon, and showed relatively better prognosis