title: Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation.
abstract: BACKGROUND
  Despite clear differences in clinical presentation and outcome, squamous cell carcinomas of the head and neck (SCCHN) arising from human papilloma virus (HPV) infection or heavy tobacco/alcohol consumption are treated equally. Next-generation sequencing is expected to reveal novel targets for more individualised treatment.
  
  
  METHODS
  Tumour specimens from 208 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity, all uniformly treated with adjuvant cisplatin-based chemoradiation, were included. A customised panel covering 211 exons from 45 genes frequently altered in SCCHN was used for detection of non-synonymous point and frameshift mutations. Mutations were correlated with HPV status and treatment outcome.
  
  
  RESULTS
  Mutational profiles and HPV status were successfully established for 179 cases. HPV- tumours showed an increased frequency of alterations in tumour suppressor genes compared to HPV+ cases (TP53 67% versus 4%, CDKN2A 18% versus 0%). Conversely, HPV+ carcinomas were enriched for activating mutations in driver genes compared to HPV- cases (PIK3CA 30% versus 12%, KRAS 6% versus 1%, and NRAS 4% versus 0%). Hotspot TP53 missense mutations in HPV- carcinomas correlated with an increased risk of locoregional recurrence (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.5-12.1, P=0.006) and death (HR 2.2, 95% CI 1.1-4.4, P=0.021). In HPV+ SCCHN, driver gene mutations were associated per trend with a higher risk of death (HR 3.9, 95% CI 0.7-21.1, P=0.11).
  
  
  CONCLUSIONS
  Distinct mutation profiles in HPV- and HPV+ SCCHN identify subgroups with poor outcome after adjuvant chemoradiation. Mutant p53 and the phosphoinositide 3-kinase pathway were identified as potential druggable targets for subgroup-specific treatment optimisation.
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Berlin, Germany; Department of Radiooncology and Radiotherapy, Charité University Hospital Berlin, Germany. Electronic address: ingeborg.tinhofer@charite.de.
authors.forename: I
authors.initials: I
authors.lastname: Tinhofer
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Berlin, Germany; Department of Radiooncology and Radiotherapy, Charité University Hospital Berlin, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Budach
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Berlin, Germany; Department of Radiooncology and Radiotherapy, Charité University Hospital Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Saki
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Berlin, Germany; Department of Radiooncology and Radiotherapy, Charité University Hospital Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Konschak
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Berlin, Germany; Department of Radiooncology and Radiotherapy, Charité University Hospital Berlin, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Niehr
authors.affiliation: Institute of Pathology, Charité-University Hospital Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Jöhrens
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Munich, Germany; Institute of Pathology, University Hospital Heidelberg and National Center for Tumor Disease, Germany; Institute of Pathology, Technical University Munich, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Weichert
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Dresden, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology (NCRO), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Linge
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Dresden, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology (NCRO), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Lohaus
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Dresden, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology (NCRO), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz-Zentrum Dresden, Rossendorf, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Krause
authors.affiliation: Institute of Biometry and Clinical Epidemiology, Charité University Hospital Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Neumann
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Munich, Germany; Institute of Pathology, University Hospital Heidelberg and National Center for Tumor Disease, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Endris
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Essen, Germany; Department of Radiotherapy, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sak
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Essen, Germany; Department of Radiotherapy, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Stuschke
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Frankfurt, Germany; Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Balermpas
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Frankfurt, Germany; Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Rödel
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Freiburg, Germany; Department of Radiation Oncology, University of Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Avlar
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Freiburg, Germany; Department of Radiation Oncology, University of Freiburg, Germany.
authors.forename: A L
authors.initials: AL
authors.lastname: Grosu
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Heidelberg, Germany; Department of Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Heidelberg Institute of Radiation Oncology (HIRO) and National Center for Radiation Research in Oncology (NCRO), Germany.
authors.forename: A
authors.initials: A
authors.lastname: Abdollahi
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Heidelberg, Germany; Department of Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Heidelberg Institute of Radiation Oncology (HIRO) and National Center for Radiation Research in Oncology (NCRO), Germany.
authors.forename: J
authors.initials: J
authors.lastname: Debus
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Munich, Germany; Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Belka
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Munich, Germany; Department of Radiation Oncology, Technical University Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Pigorsch
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Munich, Germany; Department of Radiation Oncology, Technical University Munich, Germany; Institute of Innovative Radiotherapy, Helmholtz Center Munich, Germany.
authors.forename: S E
authors.initials: SE
authors.lastname: Combs
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Tübingen; Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Tübingen, Eberhard Karls Universität Tübingen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Mönnich
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Tübingen; Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Tübingen, Eberhard Karls Universität Tübingen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Zips
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner sites, Dresden, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology (NCRO), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz-Zentrum Dresden, Rossendorf, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Baumann
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000628:therapy; D059186:Chemoradiotherapy, Adjuvant / Q000379:methods; D058534:Class I Phosphatidylinositol 3-Kinases; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005260:Female; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D027383:Papillomaviridae / Q000235:genetics; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA / Q000379:methods*; D000077195:Squamous Cell Carcinoma of Head and Neck; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014412:Tumor Virus Infections / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D058539:Phosphatidylinositol 3-Kinase; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Adjuvant chemoradiation; Cisplatin; Head and neck cancer; Human papilloma virus; Mutation profiles