Molecular characterization of oropharyngeal and oral squamous cell carcinomas

Abstract

Despite improvements in conventional therapy, the five-year survival rate has not significantly changed over the past decades and remains approximately 50%. In addition, the impact on the quality of life remains a major consideration in selecting appropriate treatment for HNSCC. Nowadays, all patients suffer from treatment-induced side effects, while only a small group respond good to the available chemotherapy. In the light of these discouraging numbers, the development of new biomarkers and targets for treatment for HNSCC are urgently needed. A better understanding of the molecular carcinogenesis of HNSCC is crucial for developing novel targets suitable for personalized and effective treatment. The aim of this thesis was to identify new molecular biomarkers in the primary tumor that have prognostic and/or predictive value and to improve treatment selection which is currently based on location and TNM classification instead of underlying tumor biology. In the first three chapters we focus on epigenetic changes, in which we studied in particular promoter hypermethylation. We showed that promoter hypermethylation plays a role in the carcinogenesis of head and neck cancer, which is more pronounced in HPV-positive oropharyngeal squamous cell carcinomas (OPSCC) compared to HPV-negative. In addition, we showed that promoter hypermethylation in HPV-negative OPSCC may play a role in the development of resistance to radiotherapy. The next three chapters focus on genetics. We looked at the mutational landscape of TP53 in the different anatomical sub-locations of head and neck cancer. Here we identified the Y220C mutation as a relative hot spot mutation in particular OPSCC. Y220C can have a predictive role in the future in the therapy of OPSCC as recently a "small molecule" is introduced which can stabilize the Y220C p53 mutant protein. Furthermore, we show that the gene copy status of oncogenes may be of clinical interest in the diagnosis of occult lymph node metastasis in patients with early oral cavity squamous cell carcinomas (OSCC) and as a prognostic biomarker. In the sixth chapter we showed that the epidermal growth factor receptor (EGFR) plays a role in the resistance of fibriblast growth factor receptor 1 (FGFR1) inhibitors in head and neck cancer. Combined treatment synergistically inhibited proliferation of resistant cell lines, providing a rationale for combining EGFR inhibitors and FGFR1 inhibitors in FGFR inhibitor resistant HNSCC patients In the last chapter, we show that in addition to genetic and epigenetic differences between HPV-positive and HPV-negative OPSCC, they also differ on immunological level In summary, this thesis shows new insights into the underlying biology of head and neck cancer, especially in OSCC and OPSCC. Better understanding of molecular characteristics of OPSCC and OSCC is an important step forward in realizing personalized cancer treatment.This will eventually improve the survival of head and neck cancer patients in the near future.