Methylation of drug resistance-related genes in chemotherapy-sensitive Epstein-Barr virus-associated gastric cancer

Hirofumi Ohmura; Mamoru Ito; Keita Uchino; Chihiro Okada; Shigeki Tanishima; Yuichi Yamada; Seiya Momosaki; Masato Komoda; Miyuki Kuwayama; Kyoko Yamaguchi; Yuta Okumura; Michitaka Nakano; Kenji Tsuchihashi; Taichi Isobe; Hiroshi Ariyama; Hitoshi Kusaba; Yoshinao Oda; Koichi Akashi; Eishi Baba

doi:10.1002/2211-5463.12765

Methylation of drug resistance-related genes in chemotherapy-sensitive Epstein-Barr virus-associated gastric cancer

FEBS Open Bio. 2020 Jan;10(1):147-157. doi: 10.1002/2211-5463.12765. Epub 2019 Dec 3.

Authors

Hirofumi Ohmura¹, Mamoru Ito¹, Keita Uchino², Chihiro Okada³, Shigeki Tanishima³, Yuichi Yamada⁴, Seiya Momosaki⁵, Masato Komoda⁶, Miyuki Kuwayama⁷, Kyoko Yamaguchi¹, Yuta Okumura⁸, Michitaka Nakano⁶, Kenji Tsuchihashi¹, Taichi Isobe¹, Hiroshi Ariyama¹, Hitoshi Kusaba¹, Yoshinao Oda⁴, Koichi Akashi¹, Eishi Baba⁹

Affiliations

¹ Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
² Department of Clinical Oncology, NTT Medical Center Tokyo, Japan.
³ Engineering Section Biomedical Informatics Development Department Kansai Division, Mitsubishi Space Software, Hyogo, Japan.
⁴ Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁵ Department of Pathology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.
⁶ Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
⁷ Department of Internal Medicine, Munakata Medical Association Hospital, Fukuoka, Japan.
⁸ Department of Internal Medicine, Kyushu University Beppu Hospital, Oita, Japan.
⁹ Department of Oncology and Social Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Abstract

Epstein-Barr virus (EBV)-associated gastric cancer (GC) is associated with a high degree of DNA methylation. However, the association between chemotherapy susceptibility and tumor DNA methylation in advanced diseases remains unclear. The comprehensive DNA methylation status of GC cells obtained from an advanced EBV-associated GC (EBVGC) case, in which complete response to S-1 plus cisplatin chemotherapy was achieved, was analyzed using a DNA methylation microarray. We compared DNA methylation of GC cells with public data and identified genes with higher methylation in EBVGC cell lines than in normal gastric cells, and genes in which methylation was increased by EBV. Of these genes, ABCG2, AHNAK2, BCL2, FZD1, and TP73 are associated with published evidence for resistance to 5-fluorouracil and cisplatin. Silencing of these genes may be associated with hypersensitivity to chemotherapy.

Keywords: DNA methylation; EBV; Epstein-Barr virus-associated gastric cancer; chemotherapy; drug susceptibility; gastric cancer.

Publication types

Case Reports

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
Antineoplastic Agents / pharmacology
Cell Line
Cisplatin / pharmacology
Cytoskeletal Proteins / genetics
DNA Methylation* / drug effects
DNA Methylation* / genetics
DNA, Neoplasm / drug effects
DNA, Neoplasm / genetics*
Drug Combinations
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics*
Fluorouracil / pharmacology
Frizzled Receptors / genetics
Gene Silencing / drug effects
Herpesvirus 4, Human / drug effects
Herpesvirus 4, Human / pathogenicity*
Humans
Male
Middle Aged
Neoplasm Proteins / genetics
Oligonucleotide Array Sequence Analysis
Oxonic Acid / pharmacology
Promoter Regions, Genetic / drug effects
Promoter Regions, Genetic / genetics
Proto-Oncogene Proteins c-bcl-2 / genetics
Stomach Neoplasms / drug therapy*
Stomach Neoplasms / genetics*
Stomach Neoplasms / virology
Tegafur / pharmacology
Tumor Protein p73 / genetics

Substances

ABCG2 protein, human
AHNAK2 protein, human
ATP Binding Cassette Transporter, Subfamily G, Member 2
Antineoplastic Agents
BCL2 protein, human
Cytoskeletal Proteins
DNA, Neoplasm
Drug Combinations
FZD1 protein, human
Frizzled Receptors
Neoplasm Proteins
Proto-Oncogene Proteins c-bcl-2
TP73 protein, human
Tumor Protein p73
S 1 (combination)
Tegafur
Oxonic Acid
Cisplatin
Fluorouracil