title: Methylation epigenotypes and genetic features in colorectal laterally spreading tumors.
abstract: Aberrant DNA methylation plays an important role in genesis of colorectal cancer (CRC). Previously, we identified Group 1 and Group 2 methylation markers through genome-wide DNA methylation analysis, and classified CRC and protruded adenoma into three distinct clusters: high-, intermediate- and low-methylation epigenotypes. High-methylation epigenotype strongly correlated with BRAF mutations and these aberrations were involved in the serrated pathway, whereas intermediate-methylation epigenotype strongly correlated with KRAS mutations. Here, we investigated laterally spreading tumors (LSTs), which are flat, early CRC lesions, through quantitative methylation analysis of six Group 1 and 14 Group 2 methylation markers using pyrosequencing. Gene mutations in BRAF, KRAS and PIK3CA, and immunostaining of TP53 and CTNNB1 as well as other clinicopathological factors were also evaluated. By hierarchical clustering using methylation information, LSTs were classified into two subtypes; intermediate-methylation epigenotype correlating with KRAS mutations (p = 9 × 10(-4)) and a granular morphology (LST-G) (p = 1 × 10(-7)), and low-methylation epigenotype correlating with CTNNB1 activation (p = 0.002) and a nongranular morphology (LST-NG) (p = 1 × 10(-7)). Group 1 marker methylation and BRAF mutations were barely detected, suggesting that high-methylation epigenotype was unlikely to be involved in LST development. TP53 mutations correlated significantly with malignant transformation, regardless of epigenotype or morphology type. Together, this may suggest that two molecular pathways, intermediate methylation associated with KRAS mutations and LST-G morphology, and low methylation associated with CTNNB1 activation and LST-NG morphology, might be involved in LST development, and that involvement of TP53 mutations could be important in both subtypes in the development from adenoma to cancer.
authors.affiliation: Department of Gastroenterology, Yokohama City University School of Medicine, Yokohama, Japan; Department of Molecular Oncology Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Sakai
authors.forename: Ken
authors.initials: K
authors.lastname: Ohata
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Chiba
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matsuhashi
authors.forename: Noriteru
authors.initials: N
authors.lastname: Doi
authors.forename: Junichi
authors.initials: J
authors.lastname: Fukushima
authors.forename: Hiroki
authors.initials: H
authors.lastname: Endo
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Takahashi
authors.forename: Shingo
authors.initials: S
authors.lastname: Tsuji
authors.forename: Koichi
authors.initials: K
authors.lastname: Yagi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Matsusaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kaneda
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000368:Aged; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
chemical_list: C495270:CTNNB1 protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: DNA methylation; KRAS; TP53; colorectal cancer; laterally spreading tumor (LST)