Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma.
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.
Goto
Yasuhiro
Y
Divisions of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Shinjo
Keiko
K
Kondo
Yutaka
Y
Shen
Lanlan
L
Toyota
Minoru
M
Suzuki
Hiromu
H
Gao
Wentao
W
An
Byonggu
B
Fujii
Makiko
M
Murakami
Hideki
H
Osada
Hirotaka
H
Taniguchi
Tetsuo
T
Usami
Noriyasu
N
Kondo
Masashi
M
Hasegawa
Yoshinori
Y
Shimokata
Kaoru
K
Matsuo
Keitaro
K
Hida
Toyoaki
T
Fujimoto
Nobukazu
N
Kishimoto
Takumi
T
Issa
Jean-Pierre J
JP
Sekido
Yoshitaka
Y
D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000368:Aged; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation; D003937:Diagnosis, Differential; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology