|Tipo di tesi||Tesi di laurea magistrale|
|Titolo||Predictive and preventive roles of BRCA1/2 testing in ovarian cancer patients|
|Titolo in inglese||Predictive and preventive roles of BRCA1/2 testing in ovarian cancer patients|
|Struttura||Dipartimento di Scienze della Vita|
|Corso di studi||BIOTECNOLOGIE MEDICHE (D.M. 270/04)|
|Data inizio appello||2022-04-12|
|Disponibilità||Accesso limitato: si può decidere quali file della tesi rendere accessibili. Disponibilità mixed (scegli questa opzione se vuoi rendere inaccessibili tutti i file della tesi o parte di essi)|
|Data di rilascio||2062-04-12|
Con l'identificazione dei geni BRCA1 e BRCA2 e del riconoscimento del loro coinvolgimento nel tumore ovarico, test molecolari sono stati implementati per l'individuazione di individui ad alto rischio di sviluppare questo tumore a causa della presenza di una variante patogenica in questi geni. Tuttavia, il ruolo di biomarker predittivo attribuito alla valutazione dello status dei geni BRCA e l'approvazione dei PARP inibitori come terapia mirata per il tumore ovarico hanno portato all'integrazione del test genetico BRCA come un passaggio necessario nel percorso diagnostico di queste pazienti.
Since the identification of BRCA1 and BRCA2 genes and the recognition of their involvement in ovarian cancer, molecular tests have been implemented for the detection of individuals at high risk of developing ovarian cancer as a result of the occurrence of a pathogenic variant in these genes. Nevertheless, the biomarker predictive role ascribed to the BRCA status and the approval of PARP inhibitors as targeted therapy for mutated ovarian cancers have brought to the integration of the BRCA genetic testing as a necessary step in the diagnostic path of these patients. This therapy has significantly changed how patients with BRCA-mutated ovarian cancer are treated and, in addition, PARP inhibitors appear to be well tolerated. Based on these evidences, this study has the purpose to retrospectively examine the comprehensive BRCA1/2 mutational scenario in the DNAs from FFPE tumor samples of 383 patients affected by ovarian cancer through Next Generation Sequencing. This test presents several issues in the clinical setting, ranging from the characteristics of FFPE specimens and the requirement of high-quality tissue, to the variant interpretation and validation processes. Despite this, somatic BRCA testing in a large cohort of patients enabled to find a broad spectrum of mutational carriers and collect information obtained regarding the mutational scenario affecting BRCA genes. The rate and the prevalence of detected variants in BRCA genes are consistent with previously published data. Moreover, knowing the somatic or germline status of clinically relevant variants can lead to the proper management of patient and treatment. In addition, in case of verified constitutional variants, relatives of these patients can enter the preventive pathway with the test execution and the possibility to implement risk reduction strategies. Furthermore, splitting patients in groups based on their family history of cancer confirmed the positive correlation between a family history for ovarian/breast cancer and the positive rate of patients for pathogenic/likely pathogenic variants and clinically relevant copy number variations. Besides, the results obtained extending the mutational analysis of BRCA-negative OC patients with a strong family history, to a germline NGS-based multigene panel test for hereditary cancer syndromes, underlined the importance to ensure investigations in these patients. Identification of a cost/time effective tool for CNV variants validation in DNA samples from FFPE specimens remains one open question for the routine of diagnostic laboratories, as well as the opportunity to test patients over time since the tumor development can lead to new genomic mutational profile. In summary, somatic BRCA testing confirmed the preventive and predictive value of this diagnostic tool for the correct management of patients affected by ovarian cancer and of their families.