title: Two subtypes of colorectal tumor with distinct molecular features in familial adenomatous polyposis.
abstract: While sporadic colorectal cancer (CRC) is classified into several molecular subtypes, stratification of familial colorectal tumors is yet to be well investigated. We previously established two groups of methylation markers through genome-wide DNA methylation analysis, which classified sporadic CRC and adenoma into three distinct subgroups: high-, intermediate-, and low-methylation epigenotypes. Here, we investigated familial adenomatous polyposis (FAP), through quantitative methylation analysis of 127 samples (16 cancers, 96 adenomas, and 15 benign mucosa from 14 patients with FAP) using six Group-1 and 14 Group-2 methylation markers, APC, BRAF, and KRAS mutation analysis, and CTNNB1 and TP53 immunohistochemical analysis. All the 14 patients presented with APC germline mutation. Three were from the same family and presented the same APC mutation. FAP tumors lacked BRAF-mutation(+) high-methylation epigenotype and were classified into two methylation epigenotypes. While 24 of 112 tumor samples showed intermediate-methylation epigenotype significantly correlating with KRAS-mutation(+) (P=3×10-4), 88 tumor samples showed low-methylation epigenotype correlating with the absence of KRAS- and BRAF-mutations. Similar to sporadic CRC, CTNNB1 was frequently activated at the adenoma stage, and TP53 mutation occurred during cancer development from adenoma. Whereas some patients showed a single epigenotype in all tumors throughout the colon, tumors with two distinct epigenotypes developed within a family with the same APC mutation or even within one patient. Methylation accumulation significantly correlated with proximal location and older age. These results indicate that there are at least two distinct molecular subtypes of FAP tumors, resembling sporadic CRC and independent from the APC germline mutation status.
authors: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.|Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.
authors: Kiyoko
authors: K
authors: Takane
authors: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Keisuke
authors: K
authors: Matsusaka
authors: Department of Pathology, Chiba University Hospital, Chiba, Japan.
authors: Satoshi
authors: S
authors: Ota
authors: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Masaki
authors: M
authors: Fukuyo
authors: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Yao
authors: Y
authors: Yue
authors: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Motoi
authors: M
authors: Nishimura
authors: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.|Department of Gastroenterology, Yokohama City University School of Medicine, Yokohama, Japan.
authors: Eiji
authors: E
authors: Sakai
authors: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Kazuyuki
authors: K
authors: Matsushita
authors: Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Hideaki
authors: H
authors: Miyauchi
authors: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Aburatani
authors: Department of Pathology, Chiba University Hospital, Chiba, Japan.|Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Yukio
authors: Y
authors: Nakatani
authors: Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.
authors: Tadatoshi
authors: T
authors: Takayama
authors: Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Hisahiro
authors: H
authors: Matsubara
authors: Division of Molecular Diagnosis, Saitama Cancer Center, Saitama, Japan.
authors: Kiwamu
authors: K
authors: Akagi
authors: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.|Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors: Atsushi
authors: A
authors: Kaneda
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D016000:Cluster Analysis; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D055815:Young Adult; D051176:beta Catenin / Q000032:analysis
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C117307:KRAS protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: CIMP; DNA methylation; KRAS; colorectal cancer; familial adenomatous polyposis (FAP)