Cancer Research, 10.1158/0008-5472.CAN-09-1595
Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively.
Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease.
Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets. [Cancer Res 2009;69(23):OF1–10]
Yasuhiro Goto1, Keiko Shinjo1,3, Yutaka Kondo1, Lanlan Shen7, Minoru Toyota8, Hiromu Suzuki9, Wentao Gao10, Byonggu An1, Makiko Fujii1, Hideki Murakami1, Hirotaka Osada1,3, Tetsuo Taniguchi5, Noriyasu Usami5, Masashi Kondo4, Yoshinori Hasegawa4, Kaoru Shimokata11, Keitaro Matsuo2, Toyoaki Hida6, Nobukazu Fujimoto12, Takumi Kishimoto12, Jean-Pierre J. Issa7 and Yoshitaka Sekido1,3
Divisions of 1 Molecular Oncology and 2 Epidemiology and Prevention, Aichi Cancer Center Research Institute; Departments of 3 Cancer Genetics and 4 Respiratory Medicine and 5 Division of General Thoracic Surgery, Nagoya University Graduate School of Medicine; 6 Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; 7 Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 8 Department of Biochemistry and 9 First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan; 10 Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 11 Department of Biomedical Sciences, Chubu University, Kasugai, Japan; and 12 Department of Respiratory Medicine, Okayama Rosai Hospital, Okayama, Japan
Key Words: DNA methylation • histone H3 lysine 27 trimethylation • malignant pleural mesothelioma • microarray
