Research Papers:

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

Caroline V.M. Verhagen, David M. Vossen, Kerstin Borgmann, Floor Hageman, Reidar Grénman, Manon Verwijs-Janssen, Lisanne Mout, Roel J.C. Kluin, Marja Nieuwland, Tesa M. Severson, Arno Velds, Ron Kerkhoven, Mark J. O’Connor, Martijn van der Heijden, Marie-Louise van Velthuysen, Marcel Verheij, Volkert B. Wreesmann, Lodewyk F.A. Wessels, Michiel W.M. van den Brekel and Conchita Vens _

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Oncotarget. 2018; 9:18198-18213. https://doi.org/10.18632/oncotarget.24797

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Caroline V.M. Verhagen1,2,*, David M. Vossen1,2,*, Kerstin Borgmann3, Floor Hageman1, Reidar Grénman4, Manon Verwijs-Janssen1, Lisanne Mout1, Roel J.C. Kluin5, Marja Nieuwland5, Tesa M. Severson6, Arno Velds5, Ron Kerkhoven5, Mark J. O’Connor7, Martijn van der Heijden1,2, Marie-Louise van Velthuysen8, Marcel Verheij1,9, Volkert B. Wreesmann2, Lodewyk F.A. Wessels10, Michiel W.M. van den Brekel2,11 and Conchita Vens1,9

1Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

2Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands

3Laboratory of Radiobiology and Experimental Radiation Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

4Department of Otorhinolaryngology, Turku University Hospital, University of Turku, Turku, Finland

5Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands

6Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

7Oncology Innovative Medicines, AstraZeneca, Saffron Walden, UK

8Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

9Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

10Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands

11Department of Oral and Maxillofacial Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

*Shared first authorship

Correspondence to:

Conchita Vens, email: [email protected]

Keywords: HNSCC; gene variants; homologous recombination; Fanconi anemia; DNA repair

Received: November 16, 2017     Accepted: February 25, 2018     Published: April 06, 2018


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.

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