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Loss of Epigenetic Control of Synuclein- Gene as a Molecular Indicator of Metastasis in a Wide Range of Human Cancers

¹ Research Service, Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA; ² Second Hospital of Nanjing City, Nanjing, China; and ³ Institute of Medicinal Biotechnology, Chinese Academy of Medicinal Sciences, Beijing, China

Requests for reprints: Jingwen Liu (154P), Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304. Phone: 650-493-5000, ext. 64411; Fax: 650-849-0251; E-mail: Jingwen.Liu{at}med.va.gov or Jian-Dong Jiang, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, 100050 Beijing, China. Phone: 86-10-63165290; Fax: 86-10-63017302; E-mail: jiandong.jiang{at}mssm.edu.

Metastasis is a major contributing factor to poor prognosis in cancer. Reliable and sensitive biomarkers that indicate the development of metastasis of primary tumors would be of great clinical use. In this study, we show that the neuronal protein synuclein- (SNCG) is abnormally expressed in a high percentage (67.5%) of tumor tissues of diversified cancer types, including liver, esophagus, colon, gastric, lung, prostate, cervical, and breast cancer, but rarely expressed in tumor-matched nonneoplastic adjacent tissues (0.6%). Expressions of SNCG protein in different cancer types all display stage-specific patterns of very low expression in stage I and high expression in stages II to IV. Importantly, we observe a strong association between SNCG protein expression in primary tumors with distant metastasis in patients regardless of the cancer type (60.6%, P < 0.001). By performing genomic sequencing and methylation-specific PCR assays, we identify an inclusive demethylation of CpG sites within the CpG island of SNCG gene in every tumor sample (100%) across all cancer types, illustrating a universal loss of the epigenetic control of SNCG gene expression in tumors and further demonstrating that the demethylation of SNCG CpG island is primarily responsible for the aberrant expression of SNCG protein in cancerous tissues. These new findings strongly suggest that reactivation of SNCG gene expression by DNA demethylation is a common critical contributing factor to malignant progression of many solid tumors and its expression in primary carcinomas is an effective molecular indicator of distant metastasis. Our studies also suggest that the methylation status of SNCG gene can be used as a sensitive molecular tool in early detections of tumorigenesis.

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