Abstract 3409: Transcription factor signature of head and neck squamous cell carcinoma

Abstract

Abstract Background: Head and Neck Squamous Cell Carcinoma (HNSCC) results in significant mortality and morbidity despite current therapeutic strategies. The molecular biology of HNSCC is related to abnormal transcriptional regulation. A direct comprehensive genome wide analysis of deregulation of key transcription factors (TF) in primary HNSCC has not been performed. In this study we sought to analyze the differences in transcription factor signatures in subtypes of cancer patients and the normal population. Methods: To evaluate the TF signatures of 44 HNSCC samples and 25 healthy oral mucosa samples we used the Affymetrix GeneChip Human Exon 1.0 ST Array data and estimated transcription levels of all genes. The TF activity signature of each of 2,600 human transcription factors was characterized by the expression of its target genes, as reflected in TRANSFAC, and corrected for methylation and CNV status. The significance of each TF based on the expression levels of its targets was compared for HPV positive (HPV+) and HPV negative (HPV-) samples. The expression of the subset of target genes of NFKB, STATs and AP1 pathways was confirmed my qRT-PCR and co-activation of NFKB and STAT3 was confirmed by Immunistochemical (IHC) analysis. Results: Of the top ranked TFs analyzed AP1, NFKB and STATs exhibited the greatest differences in TF activity in HPV+ and HPV- HNSCC tumor tissue. The changes of activity of these factors do not depend on DNA methylation or copy loss for their targets. We have confirmed coordinated activation of STAT3 and NFKB pathways in tumor samples, and showed that these pathways are the most activated in HPV- population of HNSCC patients. We have also discovered the top ten scoring genes, which expression was differentially affected by HPV infection. Expression analysis of these ten genes allows classification of HNSCC patients into three groups. Conclusions: We have discovered that HPV+ and HPV- HNSCC differ significantly based on the level of activity of the key TF, such as AP1, STATs and NFKB. These data have implications for therapeutic targeting of tumors, as well as potential insight into biologic variability of behavior and treatment response for HPV+ and HPV- HNSCC patients. Citation Format: Daria A. Gaykalova, Judi Manola, Hiroyuki Ozawa, Kathryn Morton, Justin Bishop, Michael Considine, Rajni Sharma, Chi Zhang, Elana Fertig, Marietta Tan, Patrick Hennessey, Julie Ahn, Wayne Koch, Zubair Khan, Christine H. Chung, Michael F. Ochs, Joseph A. Califano. Transcription factor signature of head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3409. doi:10.1158/1538-7445.AM2014-3409