Integrative computational analysis of transcriptional and epigenetic alterations implicates DTX1 as a putative tumor suppressor gene in HNSCC

Daria A. Gaykalova, Veronika Zizkova, Theresa Guo, Ilse Tiscareno, Yingying Wei, Rajita Vatapalli, Patrick T. Hennessey, Julie Ahn, Ludmila Danilova, Zubair Khan, Justin A. Bishop, J. Silvio Gutkind, Wayne M. Koch, William H. Westra, Elana J. Fertig, Michael F. Ochs, Joseph A. Califano

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Over a half million new cases of Head and Neck Squamous Cell Carcinoma (HNSCC) are diagnosed annually worldwide, however, 5 year overall survival is only 50% for HNSCC patients. Recently, high throughput technologies have accelerated the genome-wide characterization of HNSCC. However, comprehensive pipelines with statistical algorithms that account for HNSCC biology and perform independent confirmatory and functional validation of candidates are needed to identify the most biologically relevant genes. We applied outlier statistics to high throughput gene expression data, and identified 76 top-scoring candidates with significant differential expression in tumors compared to normal tissues. We identified 15 epigenetically regulated candidates by focusing on a subset of the genes with a negative correlation between gene expression and promoter methylation. Differential expression and methylation of 3 selected candidates (BANK1, BIN2, and DTX1) were confirmed in an independent HNSCC cohorts from Johns Hopkins and TCGA (The Cancer Genome Atlas). We further performed functional evaluation of NOTCH regulator, DTX1, which was downregulated by promoter hypermethylation in tumors, and demonstrated that decreased expression of DTX1 in HNSCC tumors maybe associated with NOTCH pathway activation and increased migration potential.

Original languageEnglish (US)
Pages (from-to)15349-15363
Number of pages15
JournalOncotarget
Volume8
Issue number9
DOIs
StatePublished - 2017

Keywords

  • DTX1
  • Expression
  • HNSCC
  • Integration
  • Methylation

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Gaykalova, D. A., Zizkova, V., Guo, T., Tiscareno, I., Wei, Y., Vatapalli, R., Hennessey, P. T., Ahn, J., Danilova, L., Khan, Z., Bishop, J. A., Silvio Gutkind, J., Koch, W. M., Westra, W. H., Fertig, E. J., Ochs, M. F., & Califano, J. A. (2017). Integrative computational analysis of transcriptional and epigenetic alterations implicates DTX1 as a putative tumor suppressor gene in HNSCC. Oncotarget, 8(9), 15349-15363. https://doi.org/10.18632/oncotarget.14856