Your browser doesn't support javascript.
loading
Fanconi anemia and homologous recombination gene variants are associated with functional DNA repair defects in vitro and poor outcome in patients with advanced head and neck squamous cell carcinoma.
Verhagen, Caroline V M; Vossen, David M; Borgmann, Kerstin; Hageman, Floor; Grénman, Reidar; Verwijs-Janssen, Manon; Mout, Lisanne; Kluin, Roel J C; Nieuwland, Marja; Severson, Tesa M; Velds, Arno; Kerkhoven, Ron; O'Connor, Mark J; van der Heijden, Martijn; van Velthuysen, Marie-Louise; Verheij, Marcel; Wreesmann, Volkert B; Wessels, Lodewyk F A; van den Brekel, Michiel W M; Vens, Conchita.
  • Verhagen CVM; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Vossen DM; Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Borgmann K; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Hageman F; Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Grénman R; Laboratory of Radiobiology and Experimental Radiation Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
  • Verwijs-Janssen M; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Mout L; Department of Otorhinolaryngology, Turku University Hospital, University of Turku, Turku, Finland.
  • Kluin RJC; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Nieuwland M; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Severson TM; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Velds A; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Kerkhoven R; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • O'Connor MJ; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • van der Heijden M; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • van Velthuysen ML; Oncology Innovative Medicines, AstraZeneca, Saffron Walden, UK.
  • Verheij M; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Wreesmann VB; Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Wessels LFA; Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • van den Brekel MWM; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Vens C; Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Oncotarget ; 9(26): 18198-18213, 2018 Apr 06.
Article en En | MEDLINE | ID: mdl-29719599
ABSTRACT
Mutations in Fanconi Anemia or Homologous Recombination (FA/HR) genes can cause DNA repair defects and could therefore impact cancer treatment response and patient outcome. Their functional impact and clinical relevance in head and neck squamous cell carcinoma (HNSCC) is unknown. We therefore questioned whether functional FA/HR defects occurred in HNSCC and whether they are associated with FA/HR variants. We assayed a panel of 29 patient-derived HNSCC cell lines and found that a considerable fraction is hypersensitive to the crosslinker Mitomycin C and PARP inhibitors, a functional measure of FA/HR defects. DNA sequencing showed that these hypersensitivities are associated with the presence of bi-allelic rare germline and somatic FA/HR gene variants. We next questioned whether such variants are associated with prognosis and treatment response in HNSCC patients. DNA sequencing of 77 advanced stage HNSCC tumors revealed a 19% incidence of such variants. Importantly, these variants were associated with a poor prognosis (p = 0.027; HR = 2.6, 1.1-6.0) but favorable response to high cumulative cisplatin dose. We show how an integrated in vitro functional repair and genomic analysis can improve the prognostic value of genetic biomarkers. We conclude that repair defects are marked and frequent in HNSCC and are associated with clinical outcome.
Palabras clave

Texto completo: 1 Banco de datos: MEDLINE Tipo de estudio: Risk_factors_studies Idioma: En Año: 2018 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Tipo de estudio: Risk_factors_studies Idioma: En Año: 2018 Tipo del documento: Article