Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway.
To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high-methylation CRC. The methylation levels of six Group-1 and 14 Group-2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development. SSA/P showed high methylation levels of both Group-1 and Group-2 markers, frequent BRAF mutation and occurrence in proximal colon, which were features of high-methylation CRC. But TSA showed low-methylation levels of Group-1 markers, less frequent BRAF mutation and occurrence at distal colon. SSA/P, but not TSA, is thus considered to be precursor of high-methylation CRC. High-methylation CRC had even higher methylation levels of some genes, e.g., MLH1, than SSA/P, and significant frequency of somatic mutations in nonsynonymous mutations (p < 0.0001) and insertion/deletions (p = 0.002). MLH1-methylated SSA/P showed lower methylation level of MLH1 compared with high-methylation CRC, and rarely accompanied silencing of MLH1 expression. The mutation frequencies were not different between MLH1-methylated and MLH1-unmethylated SSA/P, suggesting that MLH1 methylation might be insufficient in SSA/P to acquire a hypermutation phenotype. Mutations of mismatch repair genes, e.g., MSH3 and MSH6, and genes in PI3K, WNT, TGF-β and BMP signaling (but not in TP53 signaling) were significantly involved in high-methylation CRC compared with adenoma, suggesting importance of abrogation of these genes in serrated pathway.
Department of Gastroenterology, Yokohama City University School of Medicine, Yokohama, Japan.|Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Eiji
E
Sakai
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Masaki
M
Fukuyo
Department of Gastroenterology, Kanto Medical Center, NTT East, Tokyo, Japan.
Ken
K
Ohata
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Keisuke
K
Matsusaka
Department of Diagnostic Pathology, Kanto Medical Center, NTT East, Tokyo, Japan.
Noriteru
N
Doi
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Yasunobu
Y
Mano
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Kiyoko
K
Takane
Department of Pathology, Graduate School of Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
Hiroyuki
H
Abe
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Koichi
K
Yagi
Department of Gastroenterology, Kanto Medical Center, NTT East, Tokyo, Japan.
Nobuyuki
N
Matsuhashi
Department of Diagnostic Pathology, Kanto Medical Center, NTT East, Tokyo, Japan.
Junichi
J
Fukushima
Department of Pathology, Graduate School of Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
Masashi
M
Fukayama
Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan.
Kiwamu
K
Akagi
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
Hiroyuki
H
Aburatani
Department of Gastroenterology, Yokohama City University School of Medicine, Yokohama, Japan.
Atsushi
A
Nakajima
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.|CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.
Atsushi
A
Kaneda
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000236:Adenoma / Q000235:genetics* / Q000473:pathology*; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction
D014408:Biomarkers, Tumor
DNA methylation; colorectal cancer (CRC); gene mutation; sessile serrated adenoma/polyp (SSA/P); traditional serrated adenoma (TSA)