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American Head & Neck Society
Annual Meeting, April 10-11, 2013
JW Marriott Grande Lakes
Orlando, Florida

During the
Combined Otolaryngology Spring Meeting
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COLLAGEN, TYPE XIV, ALPHA 1 PROMOTER HYPERMETHYLATION IS ASSOCIATED WITH ADVANCED SALIVARY GLAND ADENOID CYSTIC CARCINOMA

Presentation: P010
Topic: Basic Science - Molecular / Cellular Biology
Type: Poster
Date: Wednesday - Thursday, April 10 - 11, 2013
Session: Designated Poster viewing times
Authors: Marietta Tan, MD, Chunbo Shao, MD, PhD, Justin A Bishop, MD, Elana J Fertig, PhD, Michael Considine, MS, William H Westra, MD, Patrick K Ha, MD
Institution(s): Departments of Otolaryngology-Head and Neck Surgery, Pathology, and Oncology Biostatistics, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Milton J. Dance Jr. Head and Neck Center, Greater Baltimore Medical Center, Baltimore, MD, USA

Background and Objectives: Salivary gland adenoid cystic carcinoma (ACC) is a rare and poorly understood malignancy of the head and neck. Epigenetic regulation via DNA promoter methylation has been shown to be an important mechanism of tumor suppressor gene (TSG) silencing in ACC. In this study, we sought to identify and validate putative TSGs under the control of promoter methylation in ACC.

Methods: ACC112, an ACC cell line, was treated with a global demethylating agent, 5-aza-2′-deoxycytidine (5-aza). Methylation and gene expression microarrays were conducted, and integrated array analysis was performed in order to identify putative TSGs that were both hypomethylated and re-expressed after 5-aza treatment. A subset of genes was selected for further validation by bisulfite sequencing in eight ACC tumors and five control salivary gland tissues. Re-expression of select genes after 5-aza treatment was assessed in two ACC cell lines. DNA methylation levels were validated by quantitative methylation-specific PCR (qMSP) in a larger cohort of ACC tumors and controls. Retrospective chart review was performed for the collection of demographic information, histopathological data, and clinical outcomes.

Results: We identified 1544 TSG candidates that were significantly hypomethylated and re-expressed after 5-aza treatment. Of these, 56 genes were selected for further validation by bisulfite sequencing. Two candidates, including collagen type XIV alpha 1 (COL14A1), were hypermethylated in ACC compared to controls. COL14A1 was also found to be significantly re-expressed in one of two ACC cell lines after 5-aza treatment. COL14A1 promoter methylation levels were therefore analyzed by qMSP in a cohort of 53 tumors and 25 controls. Twenty-eight tumors (52.8%) displayed COL14A1 hypermethylation compared to controls. The average COL14A1 methylation value was 7.28 (range 0.0-45.86) in tumors and 0.36 (range 0.0-0.83) in controls (p<0.0001). The highest methylation value of the controls was used as a cutoff to categorize the tumors into two groups for further statistical analysis: “hypomethylated” if the methylation value was less than 0.83 and “hypermethylated” if the methylation value was greater than 0.83. Univariate analysis revealed that COL14A1 hypermethylation was associated with higher tumor (T) stage at presentation (p=0.012). Seven of the 25 hypomethylated tumors (28.0%) were stage T3 or T4, whereas 19 of the 28 hypermethylated tumors (67.9%) were T3 or T4. COL14A1 methylation status was also associated with histological subtype (p=0.030). Of hypomethylated tumors, 92.0% displayed a cribriform pattern, 4% a tubular pattern, and 4% a solid pattern. In contrast, of hypermethylated tumors, 60.7% had a cribriform pattern, 17.9% a tubular pattern, and 21.4% a solid pattern. COL14A1 methylation status was not associated with tumor site, N or M stage, presence of perineural invasion, surgical margin status, or overall survival.

Conclusions: Using an integrated microarray-based approach, we identified COL14A1 as a candidate TSG that is hypermethylated in salivary gland ACC. COL14A1 hypermethylation is associated with a more advanced tumor stage and a more aggressive histologic subtype. COL14A1 is therefore a promising TSG candidate in ACC and may serve as a molecular biomarker of more aggressive tumors.

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