Laterally Spreading Type of Colorectal Adenoma Exhibits a Unique Methylation Phenotype and K-ras Mutations

Abstract

Laterally spreading tumors (LST), characterized by superficial extension along the colonic lumen, have recently been detected by colonoscopy. However, genetic and epigenetic characteristics of these tumors were scarcely reported. A total of 205 sporadic colorectal adenoma tissues (157 protruded-type, 23 granular-type LST (G-LST), 12 flat-type LST (F-LST), and 13 flat-type smaller than 1 cm) were collected. CpG island methylator phenotype (CIMP) was determined by examination of methylation status at p16, methylated in tumor (MINT) 1, 2, 12, and 31 loci. K-ras codon 12 and 13 point mutations were also examined. The relationship between macroscopic appearance and CIMP status or K-ras mutations was analyzed. Among adenomas larger than 1 cm, CpG island methylation involving 2 or more loci (CIMP-high) was more likely to be observed in G-LST (14/23, 61%) than in protruded-type adenomas (18/73, 25%) (P = .002). The prevalence of K-ras mutations in G-LST (18/23, 78%) was significantly higher than that in protruded-type adenomas (18/73, 25%) (P < .0001). Moreover, the prevalence of CIMP-high and K-ras mutations in G-LST located in the proximal colon was much higher (11/13, 85%; and 12/13, 92%, respectively). In contrast, F-LST exhibited low prevalence of CIMP-high (1/12, 8%) and K-ras mutations (2/12, 16%). High prevalence of CIMP-high and K-ras mutations in G-LST, especially in the proximal colon, could strongly suggest that G-LST appearance is associated with a unique carcinogenic pathway.