title: Flat-type colorectal advanced adenomas (laterally spreading tumors) have different genetic and epigenetic alterations from protruded-type advanced adenomas.
abstract: Morphologically, colorectal adenomas can be divided into two groups, protruded-type and flat-type. However, the accurate frequencies of genetic and epigenetic alterations in flat-type colorectal advanced adenomas (laterally spreading tumors) have remained largely unknown. In the current study, we investigated genetic and epigenetic alterations in 101 flat-type colorectal advanced adenomas and 68 protruded-type colorectal advanced adenomas by using direct DNA sequencing and quantitative real-time PCR (MethyLight), respectively. KRAS mutation was detected in a significantly higher percentage of flat-type adenomas (35%) than in protruded-type adenomas (13%). When the samples were limited to the tumors in the distal colon, the difference of KRAS mutation was still significant. KRAS mutation in G-to-A transitions at codons 12 and 13 was detected in a significantly higher percentage of flat-type adenomas (26%) than in protruded-type adenomas (9%). BRAF and beta-catenin mutations were detected in 3 and 8% of the 101 flat-type adenomas, respectively. No significant difference was found between frequencies of those mutations in flat-type adenomas and protruded-type adenomas. Methylations of MGMT, CDKN2A (p16) and MLH1 were detected in 28, 33 and 9% of the 101 flat-type adenomas, respectively. CDKN2A methylation was detected in a significantly lower percentage of flat-type adenomas than in protruded-type adenomas (63%). Methylation of at least one gene was detected in a significantly lower percentage of flat-type adenomas (54%) than in protruded-type adenomas (78%). In conclusion, KRAS mutation was frequently detected in flat-type advanced adenomas and the mutational patterns in most of them with KRAS mutations were a transition from G-to-A. Therefore, these genetic alterations seem to play an important role in the development of flat-type advanced adenomas, especially in the distal colon. Epigenetic alterations infrequently occurred in flat-type advanced adenomas, suggesting that they have different genetic and epigenetic alterations from those of protruded-type advanced adenomas.
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Taiga
authors.initials: T
authors.lastname: Takahashi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Mikami
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Nobuki
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Adachi
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000225:Adenine; D000236:Adenoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D015254:DNA Modification Methylases; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006147:Guanine; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D025803:Tumor Suppressor Protein p14ARF / Q000032:analysis / Q000235:genetics; D025521:Tumor Suppressor Proteins; D051176:beta Catenin / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D006147:Guanine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1; D018631:ras Proteins; D045643:DNA Repair Enzymes; D000225:Adenine