title: Integrated omic analysis of oropharyngeal carcinomas reveals human papillomavirus (HPV)-dependent regulation of the activator protein 1 (AP-1) pathway.
abstract: HPV-positive oropharyngeal carcinoma (OPC) patients have superior outcomes relative to HPV-negative patients, but the underlying mechanisms remain poorly understood. We conducted a proteomic investigation of HPV-positive (n = 27) and HPV-negative (n = 26) formalin-fixed paraffin-embedded OPC biopsies to acquire insights into the biological pathways that correlate with clinical behavior. Among the 2,633 proteins identified, 174 were differentially abundant. These were enriched for proteins related to cell cycle, DNA replication, apoptosis, and immune response. The differential abundances of cortactin and methylthioadenosine phosphorylase were validated by immunohistochemistry in an independent cohort of 29 OPC samples (p = 0.023 and p = 0.009, respectively). An additional 1,124 proteins were independently corroborated through comparison to a published proteomic dataset of OPC. Furthermore, utilizing the Cancer Genome Atlas, we conducted an integrated investigation of OPC, attributing mechanisms underlying differential protein abundances to alterations in mutation, copy number, methylation, and mRNA profiles. A key finding of this integration was the identification of elevated cortactin oncoprotein levels in HPV-negative OPCs. These proteins might contribute to reduced survival in these patients via their established role in radiation resistance. Through interrogation of Cancer Genome Atlas data, we demonstrated that activation of the β1-integrin/FAK/cortactin/JNK1 signaling axis and associated differential regulation of activator protein 1 transcription factor target genes are plausible consequences of elevated cortactin protein levels.
authors.affiliation: From the ‡Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7; §Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada M5T 2M9;
authors.forename: Lusia
authors.initials: L
authors.lastname: Sepiashvili
authors.affiliation: ¶Informatics & Biocomputing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3;
authors.forename: Daryl
authors.initials: D
authors.lastname: Waggott
authors.affiliation: §Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada M5T 2M9;
authors.forename: Angela
authors.initials: A
authors.lastname: Hui
authors.affiliation: §Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada M5T 2M9;
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: ‖Division of Biostatistics, University of Toronto, Toronto, Ontario, Canada M5G 2M9;
authors.forename: Susie
authors.initials: S
authors.lastname: Su
authors.affiliation: §Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada M5T 2M9;
authors.forename: Alex
authors.initials: A
authors.lastname: Ignatchenko
authors.affiliation: §Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada M5T 2M9;
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ignatchenko
authors.affiliation: §Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada M5T 2M9;
authors.forename: Marissa
authors.initials: M
authors.lastname: Laureano
authors.affiliation: **Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada M5G 2M9;
authors.forename: Shao Hui
authors.initials: SH
authors.lastname: Huang
authors.affiliation: ‖Division of Biostatistics, University of Toronto, Toronto, Ontario, Canada M5G 2M9;
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: ‡‡Department of Pathology, University of Toronto, Toronto, Ontario, Canada M5G 2C4;
authors.forename: Ilan
authors.initials: I
authors.lastname: Weinreb
authors.affiliation: **Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada M5G 2M9;
authors.forename: John
authors.initials: J
authors.lastname: Waldron
authors.affiliation: **Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada M5G 2M9;
authors.forename: Brian
authors.initials: B
authors.lastname: O'Sullivan
authors.affiliation: §§Department of Surgery, University of Toronto, Toronto, Ontario, Canada M5G 2M9;
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Irish
authors.affiliation: From the ‡Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7; ¶Informatics & Biocomputing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3; ¶¶Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: From the ‡Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7; §Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada M5T 2M9; **Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada M5G 2M9; thomas.kislinger@utoronto.ca Fei-Fei.Liu@rmp.uhn.on.ca.
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
authors.affiliation: From the ‡Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7; §Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada M5T 2M9; thomas.kislinger@utoronto.ca Fei-Fei.Liu@rmp.uhn.on.ca.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kislinger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D002277:Carcinoma / Q000150:complications / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D015331:Cohort Studies; D051356:Cortactin / Q000235:genetics* / Q000378:metabolism; D004261:DNA Replication; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D009959:Oropharyngeal Neoplasms / Q000150:complications / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D027383:Papillomaviridae / Q000502:physiology; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: C495868:CTTN protein, human; D051356:Cortactin; D019012:Integrin beta1; D018808:Transcription Factor AP-1; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D048055:Mitogen-Activated Protein Kinase 8