Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma

被引：97

作者：

Goto, Yasuhiro

Shinjo, Keiko ^{[3
]}

Kondo, Yutaka ^{[1
]}

Shen, Lanlan ^{[7
]}

Toyota, Minoru ^{[8
]}

Suzuki, Hiromu ^{[9
]}

Gao, Wentao ^{[10
]}

An, Byonggu

Fujii, Makiko

Murakami, Hideki

Osada, Hirotaka ^{[3
]}

Taniguchi, Tetsuo ^{[5
]}

Usami, Noriyasu ^{[5
]}

Kondo, Masashi ^{[4
]}

Hasegawa, Yoshinori ^{[4
]}

Shimokata, Kaoru ^{[11
]}

Matsuo, Keitaro ^{[2
]}

Hida, Toyoaki ^{[6
]}

Fujimoto, Nobukazu ^{[12
]}

Kishimoto, Takumi ^{[12
]}

Issa, Jean-Pierre J. ^{[7
]}

Sekido, Yoshitaka ^{[3
]}

机构：

[1] Aichi Canc Ctr, Res Inst, Div Mol Oncol, Chikusa Ku, Nagoya, Aichi 4648681, Japan

[2] Aichi Canc Ctr, Res Inst, Dept Epidemiol & Prevent, Nagoya, Aichi 4648681, Japan

[3] Nagoya Univ, Grad Sch Med, Dept Canc Genet, Nagoya, Aichi 4648601, Japan

[4] Nagoya Univ, Grad Sch Med, Dept Resp Med, Nagoya, Aichi 4648601, Japan

[5] Nagoya Univ, Grad Sch Med, Div Gen Thorac Surg, Nagoya, Aichi 4648601, Japan

[6] Aichi Canc Ctr Hosp, Dept Thorac Oncol, Nagoya, Aichi 464, Japan

[7] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[8] Sapporo Med Univ, Dept Biochem, Sapporo, Hokkaido, Japan

[9] Sapporo Med Univ, Dept Internal Med 1, Sapporo, Hokkaido, Japan

[10] Nanjing Med Univ, Affiliated Hosp 1, Dept Gen Surg, Nanjing, Peoples R China

[11] Chubu Univ, Dept Biomed Sci, Kasugai, Aichi 487, Japan

[12] Okayama Rosai Hosp, Dept Resp Med, Okayama, Japan

来源：

CANCER RESEARCH | 2009年 / 69卷 / 23期

基金：

日本学术振兴会;

关键词：

PROMOTER DNA METHYLATION; COMPARATIVE GENOMIC HYBRIDIZATION; COLORECTAL-CANCER; HEPATOCELLULAR CARCINOMAS; ABERRANT METHYLATION; BISULFITE PCR; GENE; METHYLTRANSFERASE; PATTERNS; CELLS;

D O I：

10.1158/0008-5472.CAN-09-1595

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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):9073-82]

引用

页码：9073 / 9082

页数：10

共 48 条

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