Abstract 4802: Cat eye syndrome chromosome region, candidate 1 (CECR1) is overexpressed and hypomethylated in salivary gland adenoid cystic carcinoma

Abstract

Abstract BACKGROUND and PURPOSE: Salivary gland adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands. It is characterized by a heterogeneous morphology, perineural invasion, and a variable clinical course. The molecular mechanisms underlying ACC are still unknown. We previously developed a high-throughput integrative epigenomic screening method to discover novel proto-oncogene candidates in ACC. With this screening method, we found that cat eye syndrome chromosome region, candidate 1 (CECR1) was a promising oncogene candidate for ACC. CECR1 encodes a member of a subfamily of the adenosine deaminase protein family and acts as a growth factor through its adenosine deaminase activity. No previous studies have correlated CECR1 in human cancers. In the current study, we validated several features of CECR1 in primary ACC samples, including promoter methylation status and expression levels. METHODS and RESULTS: Bisulfite genomic sequencing was first employed to analyze the DNA methylation levels in the promoter of CECR1 in four ACC samples and four normal salivary gland tissues. Decreased methylation in CECR1 was found in three out of four ACC samples compared to zero out of four normal tissues. Secondly, quantitative methylation specific PCR (qMSP) was performed in a larger ACC cohort including 15 ACCs and 18 normal tissues. Consistent with the bisulfite genomic sequencing results, significant demethylation of CECR1 was detected in ACC samples (methylation levels ranged from 0.1 to 300.1; median, 19.8) compared to normal tissues (range from 10.2 to 600.0; median, 235.6), p < 0.05. Thirdly, we induced global demethylation in an ACC cell line, ACC83, by 5-aza-2′-deoxycytidine/ trichostatin A (5 Aza dC/TSA) treatment. Quantitative reverse transcription PCR (qRT-PCR) showed that CECR1 was significantly re-expressed in 5 Aza dC/TSA treated cell lines. Lastly, we analyzed the expression levels of CECR1 by qRT-PCR in the same ACC cohort. We found significant overexpression of CECR1 in ACCs compared to normal salivary tissue, p < 0.05. CONCLUSIONS: This is the first study to associate elevated CECR1 levels with salivary gland ACC. The transcription of CECR1 appears to be upregulated by promoter demethylation. Both overexpression and promoter hypomethylation of CECR1 are hallmarks of ACC. CECR1 might play an important role in salivary gland ACC. FUTURE DIRECTIONS: Functional studies of CECR1's role(s) in the carcinogenesis of salivary gland ACC are underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4802. doi:10.1158/1538-7445.AM2011-4802