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Digital archive of theses discussed at the University of Pisa


Thesis etd-08202021-140104

Thesis type
Tesi di dottorato di ricerca
Thesis title
Whole-exome analysis in osteosarcoma: a translational research approach to identify a personalized therapy
Academic discipline
Course of study
tutor Prof. Franchi, Alessandro
commissario Dott.ssa Mazzanti, Chiara Maria
  • next generation sequencing
  • osteosarcoma
  • target therapy
  • whole exome
Graduation session start date
Release date
Osteosarcoma (OS) is the most common primary cancer of bone and it typically affects the extremities of adolescents. The current standard of care is associated with considerable adverse effects. Surgeries include amputation or complex limb-sparing procedures that markedly affect the quality of life. High doses of classic chemotherapy are associated with major toxicities due to the lack of specificity, which may cause cardiac dysfunction, ototoxicity, infertility and secondary malignancies.
The aim of the project is to perform analyses with Next Generation Sequencing (NGS) methods, in particular whole-exome sequencing (WES), to identify essential gene alterations in OS with the potential to be clinically actionable.
The study consists of histological and molecular analysis on biological material collected from patients affected by conventional high-grade OS. The number of subjects included in the study is 22, ranging in age between 8 and 34 years. The histological evaluation of chemotherapy induced tumor necrosis showed a slight prevalence of good (GR) over poor (PR) responders (12 vs 10). Statistical analysis on the follow-up highlights that a good response to therapy is a significant positive prognostic factor for disease-free survival compared with a poor response. We analysed the exome of 19 out of 22 biopsy samples. The most promising results are the identification of mutations that are associated with a worse prognosis, such as BRCA2, CREBBP, ARID1A and RAD50. This could be critical for early prognosis assessment and to determine a more specific therapy for subjects harbouring these mutations. A prompt test may be the immunohistochemical investigation of pre-treatment biopsies. Since several studies have shown that neoplasms harbouring PARP and BRCA mutations are significantly susceptible to a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP), patients with these mutations might benefit from personalised targeted therapy. Finally, patients with a mutational profile associated with a better prognosis may avoid heavy non-specific therapies leading to several side effects.