title: IL-10 and integrin signaling pathways are associated with head and neck cancer progression.
abstract: BACKGROUND
  Head and neck cancer is morbid with a poor prognosis that has not significantly improved in the past several decades. The purpose of this study was to identify biological pathways underlying progressive head and neck cancer to inform prognostic and adjuvant strategies. We identified 235 head and neck cancer patients in The Cancer Genome Atlas (TCGA) with sufficient clinical annotation regarding therapeutic treatment and disease progression to identify progressors and non-progressors. We compared primary tumor gene expression and mutational status between these two groups.
  
  
  RESULTS
  105 genes were differentially expressed between progressors and nonprogressors (FDR < 0.05). Pathway analyses revealed deregulation (FDR < 0.05) of multiple pathways related to integrin signaling as well as IL-10 signaling. A number of genes were uniquely mutated in the progressor cohort including increased frequency of truncating mutations in CTCF (P = 0.007). An 11-gene signature derived from a combination of unique mutations and differential expression was identified (PAGE4, SMTNL1, VTN, CA5A, C1orf43, KRTAP19-1, LEP, HRH4, PAGE5, SEZ6L, CREB3). This signature was associated with decreased overall survival (Logrank Test; P = 0.03443). Cox modeling of both key clinical features and the signature was significant (P = 0.032) with the greatest prognostic improvement seen in the model based on nodal extracapsular spread and alcohol use alone (P = 0.004).
  
  
  CONCLUSIONS
  Molecular analyses of head and neck cancer tumors that progressed despite treatment, identified IL-10 and integrin pathways to be strongly associated with cancer progression. In addition, we identified an 11-gene signature with implications for patient prognostication. Mutational analysis highlighted a potential role for CTCF, a crucial regulator of long-range chromatin interactions, in head and neck cancer progression.
authors.affiliation: Department of Radiation Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. bornstei@ohsu.edu.
authors.forename: Sophia
authors.initials: S
authors.lastname: Bornstein
authors.affiliation: Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University 3, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. schmidma@ohsu.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: OHSU Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. choonoo@ohsu.edu.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Choonoo
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. levint@ohsu.edu.
authors.forename: Trevor
authors.initials: T
authors.lastname: Levin
authors.affiliation: OHSU Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. grayjo@ohsu.edu.|Department of Biomedical Engineering, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. grayjo@ohsu.edu.
authors.forename: Joe
authors.initials: J
authors.lastname: Gray
authors.affiliation: Department of Radiation Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. thomasch@ohsu.edu.|OHSU Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. thomasch@ohsu.edu.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Thomas
authors.affiliation: Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University 3, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. wongme@ohsu.edu.|OHSU Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. wongme@ohsu.edu.
authors.forename: Melissa
authors.initials: M
authors.lastname: Wong
authors.affiliation: OHSU Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. mcweeney@ohsu.edu.|Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. mcweeney@ohsu.edu.|Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. mcweeney@ohsu.edu.
authors.forename: Shannon
authors.initials: S
authors.lastname: McWeeney
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000076246:CCCTC-Binding Factor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016023:Integrins / Q000235:genetics* / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C508609:IL10 protein, human; D016023:Integrins; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D016753:Interleukin-10