title: Molecular dissection of premalignant colorectal lesions reveals early onset of the CpG island methylator phenotype.
abstract: The concept of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) is widely accepted, although the timing of its occurrence and its interaction with other genetic defects are not fully understood. Our aim in this study was to unravel the molecular development of CIMP cancers by dissecting their genetic and epigenetic signatures in precancerous and malignant colorectal lesions. We characterized the methylation profile and BRAF/KRAS mutation status in 368 colorectal tissue samples, including precancerous and malignant lesions. In addition, genome-wide copy number aberrations, methylation profiles, and mutations of BRAF, KRAS, TP53, and PIK3CA pathway genes were examined in 84 colorectal lesions. Genome-wide methylation analysis of CpG islands and selected marker genes revealed that CRC precursor lesions are in three methylation subgroups: CIMP-high, CIMP-low, and CIMP-negative. Interestingly, a subset of CIMP-positive malignant lesions exhibited frequent copy number gains on chromosomes 7 and 19 and genetic defects in the AKT/PIK3CA pathway genes. Analysis of mixed lesions containing both precancerous and malignant components revealed that most aberrant methylation is acquired at the precursor stage, whereas copy number aberrations are acquired during the progression from precursor to malignant lesion. Our integrative genomic and epigenetic analysis suggests early onset of CIMP during CRC development and indicates a previously unknown CRC development pathway in which epigenetic instability associates with genomic alterations.
authors.affiliation: First Department of Internal Medicine, the Research Institute for Frontier Medicine, Sapporo Medical University, Japan.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Hiro-o
authors.initials: HO
authors.lastname: Yamano
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.forename: Masanori
authors.initials: M
authors.lastname: Nojima
authors.forename: Seiko
authors.initials: S
authors.lastname: Kamimae
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sawada
authors.forename: Masami
authors.initials: M
authors.lastname: Ashida
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kimura
authors.forename: Ryo
authors.initials: R
authors.lastname: Takagi
authors.forename: Taku
authors.initials: T
authors.lastname: Harada
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Akiko
authors.initials: A
authors.lastname: Sato
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kai
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sugai
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
mesh_terms: D000368:Aged; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D018450:Disease Progression; D004724:Endoscopy; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; 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