title: NF-κB and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma.
abstract: Using high-throughput analyses and the TRANSFAC database, we characterized TF signatures of head and neck squamous cell carcinoma (HNSCC) subgroups by inferential analysis of target gene expression, correcting for the effects of DNA methylation and copy number. Using this discovery pipeline, we determined that human papillomavirus-related (HPV+) and HPV- HNSCC differed significantly based on the activity levels of key TFs including AP1, STATs, NF-κB and p53. Immunohistochemical analysis confirmed that HPV- HNSCC is characterized by co-activated STAT3 and NF-κB pathways and functional studies demonstrate that this phenotype can be effectively targeted with combined anti-NF-κB and anti-STAT therapies. These discoveries correlate strongly with previous findings connecting STATs, NF-κB and AP1 in HNSCC. We identified five top-scoring pair biomarkers from STATs, NF-κB and AP1 pathways that distinguish HPV+ from HPV- HNSCC based on TF activity and validated these biomarkers on TCGA and on independent validation cohorts. We conclude that a novel approach to TF pathway analysis can provide insight into therapeutic targeting of patient subgroup for heterogeneous disease such as HNSCC.
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Daria A
authors: DA
authors: Gaykalova
authors: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA.
authors: Judith B
authors: JB
authors: Manola
authors: Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Hiroyuki
authors: H
authors: Ozawa
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.|Laboratory of Molecular Pathology, Institute of Molecular and Translational Medicine, Palacky University, Olomouc, Czech Republic.
authors: Veronika
authors: V
authors: Zizkova
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Kathryn
authors: K
authors: Morton
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.|Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Justin A
authors: JA
authors: Bishop
authors: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Rajni
authors: R
authors: Sharma
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.|University of Virginia, Charlottesville, VA.
authors: Chi
authors: C
authors: Zhang
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Christina
authors: C
authors: Michailidi
authors: Division of Oncology Biostatistics, Johns Hopkins Medical Institutions, Baltimore, MD.|Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Michael
authors: M
authors: Considine
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Marietta
authors: M
authors: Tan
authors: Division of Oncology Biostatistics, Johns Hopkins Medical Institutions, Baltimore, MD.|Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Elana J
authors: EJ
authors: Fertig
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.|Mid-Michigan Ear, Nose, and Throat, East Lansing, MI.
authors: Patrick T
authors: PT
authors: Hennessey
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Julie
authors: J
authors: Ahn
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Wayne M
authors: WM
authors: Koch
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.|Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: William H
authors: WH
authors: Westra
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Zubair
authors: Z
authors: Khan
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.|Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD.
authors: Christine H
authors: CH
authors: Chung
authors: Division of Oncology Biostatistics, Johns Hopkins Medical Institutions, Baltimore, MD.|Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD.|Department of Mathematics and Statistics, The College of New Jersey, Ewing, NJ.
authors: Michael F
authors: MF
authors: Ochs
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD.|Milton J. Dance Head and Neck Center, Greater Baltimore Medical Center, Baltimore, MD.
authors: Joseph A
authors: JA
authors: Califano
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D006801:Humans; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D030361:Papillomavirus Infections / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: HNSCC; HPV; NF-κB; STAT3; transcription factor