title: CpG island methylation is frequently present in tubulovillous and villous adenomas and correlates with size, site, and villous component.
abstract: CpG island methylator phenotype (CIMP) pathway in colorectal cancer is characterized by methylation of promoter regions of multiple putative tumor suppressor genes. Aberrant methylation also occurs in serrated and adenomatous polyps. We examined 32 tubulovillous/villous adenomas and 30 tubular adenomas for BRAF/KRAS mutations and methylation at hMLH1, p16, HIC1, RASSF2, MGMT, MINT1, and MINT31. CIMP-positive status (methylation at 3 or more loci) was observed in 44% tubulovillous/villous adenomas compared with 8 (27%) of 30 tubular adenomas (P = .08). Tubulovillous/villous adenomas showed significantly higher methylation than tubular adenomas at MGMT (87% vs 37%, P < .01) and RASSF2 (94% vs 70%, P = .02). There was no significant difference in methylation of HIC1, MINT1, MINT31, and p16. hMLH1 methylation was absent in all tubulovillous/villous adenomas and seen in only 2 (7%) tubular adenomas. CIMP-positive status correlated with large size, right-sided location, and amount of villous component in tubulovillous/villous adenomas. BRAF V600E mutation was not observed in any tubular adenoma or tubulovillous/villous adenoma. KRAS mutations were seen in 9% of tubulovillous/villous adenomas and 10% of tubular adenomas. In conclusion, CIMP-positive phenotype is common in tubulovillous/villous adenomas and increases with large size, right-sided location, and amount of villous component. Methylation of MGMT and RASSF2 increases during the progression from tubular adenoma to tubulovillous/villous adenoma. BRAF mutations are absent in tubulovillous/villous adenomas.
authors.affiliation: Department of Pathology, Veteran Affairs Medical Center and University of California at San Francisco, San Francisco, CA 94121, USA. sanjay.kakar@ucsf.edu
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kakar
authors.forename: Guoren
authors.initials: G
authors.lastname: Deng
authors.forename: Lisa
authors.initials: L
authors.lastname: Cun
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Sahai
authors.forename: Young S
authors.initials: YS
authors.lastname: Kim
mesh_terms: D018253:Adenoma, Villous / Q000235:genetics* / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D006801:Humans; D053842:Microsatellite Instability; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins