Homologous Recombination Ovarian Cancer

The study is conducted on a cohort of patient from the female population of North Sardinia. Aim of the project is the identification of new prognostic and predictive markers of therapeutic response in patients with advanced ovarian cancer by identifying alterations in homologous recombination (HRD) in the Sardinian population.

The rapid development of innovative technologies has allowed a considerable broadening of knowledge about genetic aspects related to BRCA genes and their role in the homologous recombination (HR) DNA repair mechanism. It is known that genetic and epigenetic events can cause inactivation of other components of the HR pathway, in addition to the BRCA1 and BRCA2 genes, causing a deficit of such repair mechanisms (Homologous Recombination Deficiency, HRD) in sporadic tumors.

Currently one of the main challenges for the future is to define HRD status in patients with ovarian cancer but with BRCAness phenotype.

The status of the DNA repair system, deficient or proficient, influences the therapeutic choice, determining the sensitivity of cancer cells to PARP inhibitors. The understanding of the prognostic and predictive value of HRD in advanced ovarian cancer is not yet so well explored.

The study is based on genomic mutational profiling through Next Generation Sequencing using the Oncomine^TM Comprehensive Assay Plus panel (Thermofisher Scientific) that allows the sequencing of more than 500 genes implicated in cancer research, providing, on one hand, information about the presence of mutations predisposing to ovarian cancer in the BRCA1 and BRCA2 genes and, on the other, the characterisation of mutations in other 44 genes likely to be involved in HR. The presence of LOH (loss of genomic heterozygosity) of other genes and the identification of the Copy Number Variations allow to establish a robust Genomic Instability prediction algorithm (GIM score) as a new prognostic and predictive marker of response to PARP inhibitors therapy.

The molecular analysis will be conducted on an FFPE archive of 50 cases of ovarian cancer from a female population of North Sardinia. Sardinian population, which, for geographical and historical reasons, has been isolated for long times and, even within different local ethnic groups, is genetically homogenous, is therefore a model that is able to help the definition of genetic factors underlying complex and/or multifactorial diseases such as cancer.

The predictive score of genomic instability will be compared with data obtained from a group of control cases (Validation Cohort) analysed with other NGS platforms.

The project is coordinated by Maria Cristina Sini, C.N.R. – Institute of Genetic and Biomedical Research (IRGB)-Sassari Unit

Partners: Ospital University Health Unit, Sassari