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Tesi etd-11222019-145430


Thesis type
Tesi di specializzazione (5 anni)
Author
GONNELLI, ALESSANDRA
URN
etd-11222019-145430
Title
The role of single nucleotide polymorphisms (SNPs) in glioblastoma patients treated with concomitant radiochemotherapy
Struttura
RICERCA TRASLAZIONALE E DELLE NUOVE TECNOLOGIE IN MEDICINA E CHIRURGIA
Corso di studi
RADIOTERAPIA
Supervisors
relatore Prof. Paiar, Fabiola
correlatore Dott. Pasqualetti, Francesco
Parole chiave
  • single nucleotide polymorphisms
  • glioblastoma
Data inizio appello
11/12/2019;
Consultabilità
Secretata d'ufficio
Data di rilascio
11/12/2089
Riassunto analitico
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults and it has a poor prognosis. Nowadays, the treatment of GBM remains difficult and no treatment is curative. Since 2005 the standard treatment for these patients has been surgery followed by radiotherapy (RT) with concomitant and adjuvant chemotherapy using the DNA alkylating agent temozolomide (TMZ), and both treatments induce DNA damage. However, within a year from the end of the upfront therapy most patients have a relapse of the disease and nowadays no second-line treatment can improve the overall survival (OS) of these patients.
Owing to the dismal prognosis faced by patients suffering from this disease, there is a strong need to identify new targets that might improve therapy.
Genotoxic agents such as ionizing radiation can modify biological molecules, including DNA, by a direct or indirect mechanism the latter using the generation of reactive oxygen species (ROS). This may cause harmful mutations more easily than cell damage.
The homologous recombination DNA repair (HRR) pathway, the base excision repair (BER) mechanism, and the antioxidative enzymes are necessary as defense-mechanisms against these DNA damaging agents.
For instance, base excision repair (BER) requires action of XRCC1. Additionally, XRCC3 and RAD51 recombinases are required for homologous recombination DNA repair (HRR) and for DNA double-strand break (DNA-DSB) repair pathways. Furthermore, glutathione S-transferases (GSTs) are involved in the detoxification of oxidative stress damage. Genetic polymorphisms and mutations in the GSTP1, RAD51, XRCC1 and XRCC3 genes have been studied in the context of tumor genesis and in radio- and chemo-resistance in several solid tumors.
GSTP1, XRCC1, XRCC3 and RAD51 proteins are essential components of antioxidation, BER and HRR of DNA, respectively. Deficiencies in BER, HRR and antioxidation pathways are involved in the progression of cancer. In this prospective study, we carried out a pharmacogenetic evaluation of the role of selected XRCC1, XRCC3, RAD51 and GSTP-1 Single Nucleotide Polymorphisms (SNPs) as possible biomarkers for the survival and response in GBM patients treated with combined post-operative upfront RT-CT.
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