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Patients with head and neck squamous cell carcinoma (HNSCC) often present at an advanced stage. They are treated with a combination of platinum-based drugs and radiotherapy. Unfortunately, a large proportion does not benefit from the treatment and many patients suffer from severe side effects. In this thesis we aimed to improve personalized treatment of HNSCC patients.Prompted by the relevance of DNA repair defects in breast cancer and the high incidence of HNSCC in Fanconi anemia patients with a germline mutation in one of their DNA repair genes, we investigated the incidence and role of such defects. In a panel of 29 HNSCC cell lines, DNA repair defects were identified by functional assays and sequencing identified the potential genetic causes. We showed that selection of DNA sequence variants, based on homozygosity and SNP allele frequency, is crucial to identify functional DNA repair defects. Our patient cohort showed a prevalence of 19% of such variants. Importantly these patients do worse, but their prognosis improves with increased doses of platinum drugs. We aimed at exploiting these defects by treatment with a poly (ADP-ribose) polymerase inhibitor (PARPi) and found that radiosensitization by the PARPi olaparib occurs at a much lower dose in DNA repair deficient tumor cells.Lastly, we looked into the important biomarker human papillomavirus (HPV) that predicts better overall survival. We show that tumors with transcriptionally inactive HPV resemble HPV-negative tumors in that these patient groups have a comparable survival.Together, these findings help to improve personalized treatment for HNSCC patients.

In de afgelopen decennia zijn er opmerkelijke veranderingen opgetreden in de epidemiologie van het plaveiselcelcarcinoom in het hoofd-halsgebied (HNSCC). Naast de typische HNSCC patiënt (man, 60-70 jaar, nicotine- en alcohol-abusus) is er meer aandacht gekomen voor de jonge HNSCC patiënt (