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
Publication year
2018Author(s)
Source
Oncotarget, 9, 26, (2018), pp. 18198-18213ISSN
Publication type
Article / Letter to editor

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Organization
Radiation Oncology
Journal title
Oncotarget
Volume
vol. 9
Issue
iss. 26
Page start
p. 18198
Page end
p. 18213
Subject
Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health SciencesAbstract
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.
This item appears in the following Collection(s)
- Academic publications [227437]
- Electronic publications [107154]
- Faculty of Medical Sciences [86157]
- Open Access publications [76289]
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