Half a million new cases of Head and Neck Squamous Cell Carcinoma (HNSCC) are diagnosed annually worldwide. Given the advanced stage at diagnosis, 5 year survival after initial diagnosis is only 50% for HNSCC patients despite the current therapeutic strategies.

Recently, high throughput technologies have accelerated the genome-wide characterization of HNSCC, but given the high sensitivity of this methodology, these data require careful evaluation. To improve the detection of cancer-related changes in HNSCC we applied outlier statistics to high throughput DNA methylation and gene expression data, and identified 76 top-scoring candidate proto-oncogenes and tumor suppressor genes with significantly changed expression in tumors compared to normal tissues. We identified epigenetically regulated candidates with potential role in HNSCC by selecting genes with strong negative correlation between gene expression and DNA methylation of their promoters. Differential expression and methylation of selected candidates were confirmed with assays on an independent HNSCC cohort and on public domain high throughput data on TCGA-HNSCC cohort (The Cancer Genome Atlas). We further performed functional evaluation of a lead candidate - DTX1 and demonstrated that DTX1 is a negative regulator of cell migration. We confirmed that epigenetic-dependent downregulation of DTX1 enhanced invasiveness of head and neck cancer cells.

Outlier analysis integrated with high throughput expression and methylation can be used to identify an epigenetically- regulated tumor suppressor genes, including DTX1.

Citation Format: Daria A. Gaykalova, Veronika Zizkova, Ilse Tiscareno, Yingying Wei, Rajita Vatapalli, Patrick T. Hennessey, Julie Ahn, Ludmila V. Danilova, Zubair Khan, Justin A. Bishop, Wayne M. Koch, William H. Westra, Michael F. Ochs, Joseph A. Califano. DTX1 is an epigenetically regulated tumor suppressor gene discovered by integrative analysis of epigenetic and transcriptional alterations in HNSCC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 815. doi:10.1158/1538-7445.AM2015-815

©2015 American Association for Cancer Research.
2015