title: DNA methylation status of a distinctively different subset of genes is associated with each histologic Lauren classification subtype in early gastric carcinogenesis.
abstract: DNA methylation change is known to play a crucial role in early gastric carcinogenesis. The present study aimed to identify and validate the correlation between differentially methylated regions (DMRs) and the subtypes of early gastric cancers (EGCs). Illumina Infinium methylation assay (IIMA; 450K BeadChip kit) was performed on fresh tumor and non‑tumor tissues of 12 EGCs to screen the methylation status of 450,000 CpG sites. To evaluate the significance of DNA methylation in each histologic subtype, pyrosequencing assay (PA) was performed on 38 EGCs (18 intestinal-, 12 mixed- and 8 diffuse-type) using 12 genes selected from the screening. Between tumors of the intestinal-type (n=6), and diffuse- (n=4) plus mixed-types (n=2), 169 regions showed significant differences (intensity>3,000, Δβ>0.2) in IIMA. Hierarchical clustering using the 169 DMRs revealed distinct separation between the two groups. In PA using 12 selected genes from the IIMA results, the aberrant methylation statuses of DVL2 (p=0.0186) and ETS1 (p=0.0222) were significantly related to diffuse- and mixed-types rather than the intestinal-type, while C19orf35 (p=0.019) and CNRIP1 (p=0.0473) were related to the diffuse‑type rather than intestinal‑type, and GAL3ST2 (p=0.0158) and ITGA3 (p=0.0273) were related to the mixed-type rather than the other two types. The methylation of other genes, CLIP4, XKR6, CCDC57, MAML3 and SDC2, was related with age, tumor location, or Helicobacter infection rather than the histologic subtype. Aberrant DNA methylation of certain genes may be independently involved in each histologic subtype of EGC. Furthermore, mixed-type EGCs may be a distinctive histologic subtype based on the different subset of DMRs compared to those of other subtypes.
authors.affiliation: Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Yosep
authors.initials: Y
authors.lastname: Chong
authors.affiliation: Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Khalilullah
authors.initials: K
authors.lastname: Mia-Jan
authors.affiliation: Department of Surgery, Yonsei University, Wonju College of Medicine, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.affiliation: Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Jamshid
authors.initials: J
authors.lastname: Abdul-Ghafar
authors.affiliation: Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Jijgee
authors.initials: J
authors.lastname: Munkhdelger
authors.affiliation: Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Sayamaa
authors.initials: S
authors.lastname: Lkhagvadorj
authors.affiliation: Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju, Gangwon-do, Republic of Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Jung
authors.affiliation: Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Mira
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Ji
authors.affiliation: Division of Statistics, Institute of Life Style Medicine, Yonsei University, Wonju College of Medicine, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Choi
authors.affiliation: Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju, Gangwon-do, Republic of Korea.
authors.forename: Mee-Yon
authors.initials: MY
authors.lastname: Cho
mesh_terms: D000230:Adenocarcinoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D016481:Helicobacter Infections; D016480:Helicobacter pylori; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology