Profiling epigenetic inactivation of tumor suppressor genes in tumors and plasma from cutaneous melanoma patients

被引:180
作者
Hoon, DSB
Spugnardi, M
Kuo, C
Huang, SK
Morton, DL
Taback, B
机构
[1] St Johns Hlth Ctr, John Wayne Canc Inst, Dept Mol Oncol, Santa Monica, CA 90404 USA
[2] St Johns Hlth Ctr, John Wayne Canc Inst, Div Surg Oncol, Santa Monica, CA 90404 USA
关键词
MGMT; RAR-beta; 2; RASSF1A; methylation; melanoma;
D O I
10.1038/sj.onc.1207505
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Aberrant methylation of CpG islands in promoter regions of tumor suppressor genes (TSG) has been demonstrated in epithelial origin tumors. However, the methylation pro. ling of tumor-related gene promoter regions in cutaneous melanoma tumors has not been reported. Seven known or candidate TSGs that are frequently hypermethylated in carcinomas were assessed by methylation-specific polymerase chain reaction (MSP) in 15 melanoma cell lines and 130 cutaneous melanoma tumors. Four TSGs were frequently hypermethylated in 86 metastatic tumor specimens: retinoic acid receptor-beta2 (RAR-beta2) (70%), RAS association domain family protein 1A (RASSF1A) (57%), and O-6-methylguanine DNA methylatransferase (MGMT) (34%), and death-associated protein kinase (DAPK) (19%). Hypermethylation of MGMT, RASSF1A, and DAPK was significantly lower in primary melanomas (n = 20) compared to metastatic melanomas. However, hypermethylation of RAR-beta2 was 70% in both primary and metastatic melanomas. Cell lines had hypermethylation profiles similar to those of metastatic melanomas. The analysis of these four markers of metastatic tumors demonstrated that 97% had greater than or equal to1 gene(s) and 59% had greater than or equal to2 genes hypermethylated. The methylation of genes was verified by bisulfite sequencing. The mRNA transcripts could be re-expressed in melanoma cell lines having hypermethylated genes following treatment with 5'-aza 2'-deoxycytidine (5Aza-dC). Analysis of melanoma patients' plasma (preoperative blood; n = 31) demonstrated circulating hypermethylated MGMT, RAR-beta2, and RASSF1A DNA for at least one of the markers in 29% of the patients. Our findings indicate that the incidence of TSG hypermethylation increases during tumor progression. Methylation of TSG may play a significant role in cutaneous melanoma progression.
引用
收藏
页码:4014 / 4022
页数:9
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