Methylation-Induced Silencing of ASC/TMS1, a Pro-Apoptotic Gene, is a Late-Stage Event in Colorectal Cancer

Marco A. Riojas, Mingzhou Guo, Sabine C. Glöckner, Emi Ota Machida, Stephen B. Baylin and Nita Ahuja

volume 6 | issue 11

November 2007
Pages: 1710 - 1716

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The hypermethylation of tumor-suppressor gene promoter regions has been shown to result in the epigenetic inactivation of many genes. ASC/TMS1 is a pro-apoptotic gene that has been shown to be methylated in many different human neoplasms. The methylation status of ASC/TMS1 was analyzed in a series of colorectal cancer (CRC) cell lines, primary colorectal adenomas and cancers, and normal colorectal tissue samples using methylation-specific PCR (MSP). The gene expression of ASC/TMS1 in the CRC cell lines was analyzed using reverse-transcriptase PCR (RT-PCR). Methylation analysis showed complete methylation of ASC/TMS1 in 5 of 7 (71%) CRC cell lines. RT-PCR showed absence of mRNA expression in these same cell lines, and expression was restored after treatment with the demethylating drug 5-aza-2’-deoxyazacytidine. The two unmethylated cell lines showed ASC/TMS1 mRNA expression both before and after treatment with 5-aza-2’-deoxyazacytidine. Methylation was seen in 20 of 115 (17%) of primary colorectal cancer specimens, but no methylation was seen in 30 colorectal adenomas and 11 normal colorectal tissue samples. Methylation status of ASC/TMS1 was correlated with a series of clinicopathological variables using multivariate analysis. Methylation of ASC/TMS1 was more common in right-sided tumors (p = 0.02), concordant with hMLH1 methylation (p=0.03) and is a late stage event, occurring in 0 of 18 tubular adenomas, 0 of 12 villous adenomas, 2 of 44 (5%) Stage 1 cancers, 8 of 31 (26%) Stage 2 cancers, 8 of 21 (38%) Stage 3 cancers, and 2 of 19 (11%) Stage 4 cancers. The ASC/TMS1 gene is frequently silenced in CRC due to promoter hypermethylation. Methylation of ASC/TMS1 appears to be a late-stage event in colorectal carcinogenesis associated with invasive carcinomas but not with normal colorectal tissue or colorectal adenomas. Methylation of ASC/TMS1 may have implications for cancer prognosis.

Authors

Marco A. Riojas

Department of Surgery, Johns Hopkins University, Baltimore, MD

Mingzhou Guo

Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore MD

Sabine C. Glöckner

Department of Surgery, Johns Hopkins University, Baltimore, MD

Emi Ota Machida

Department of Oncology, Johns Hopkins University, Baltimore, MD

Stephen B. Baylin

The Johns Hopkins University Medical Institutions, Baltimore, Maryland

Nita Ahuja

Department of Surgery and Oncology, Johns Hopkins University, Baltimore, MD

We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link: