Oncotarget

Research Papers:

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 and Joseph A. Califano _

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Oncotarget. 2017; 8:15349-15363. https://doi.org/10.18632/oncotarget.14856

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Abstract

Daria A. Gaykalova1, Veronika Zizkova1,2, Theresa Guo1, Ilse Tiscareno1, Yingying Wei3,10, Rajita Vatapalli1,4, Patrick T. Hennessey1,5, Julie Ahn1, Ludmila Danilova3,11, Zubair Khan1, Justin A. Bishop1,6, J. Silvio Gutkind7, Wayne M. Koch1, William H. Westra1,6, Elana J. Fertig3, Michael F. Ochs3,8, Joseph A. Califano1,9

1Department of Otolaryngology—Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

2Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic

3Division of Oncology Biostatistics, Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

4Department of Urology, Northwestern University, Chicago, Illinois, USA

5Department of Otolaryngology, Mid-Michigan Ear Nose and Throat, East Lansing, Michigan, USA

6Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

7Department of Pharmacology, UC San Diego Moores Cancer Center, La Jolla, California, USA

8Department of Mathematics and Statistics, The College of New Jersey, Ewing, New Jersey, USA

9Department of Surgery, UC San Diego, Moores Cancer Center, La Jolla, California, USA

10Department of Statistics, The Chinese University of Hong Kong, NT, Shatin, Hong Kong

11Laboratory of Systems Biology and Computational Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia

Correspondence to:

Joseph A. Califano, email: [email protected]

Daria A. Gaykalova, email: [email protected]

Keywords: HNSCC, DTX1, expression, methylation, integration

Received: September 07, 2016     Accepted: January 16, 2017     Published: January 27, 2017

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.


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