The role of polymorphisms occurring in <i>BRCA1</i>/2 genes in determining ovarian cancer risk.
Authors: Marta Castiglia, Lorena Incorvaia, Alessandro Perez, Chiara Brando, Antonio Galvano, Nadia Barraco, Valentina Calò, Daniela Cancelliere, Alessia Fiorino, Alessia Pivetti, Erika Pedone, Delia Sardo, Sara Inguglia, Jole di Marco, Marco Bono, Daniele Fanale, Anna Paola Carreca, Ignazio Ugo Carreca, Antonio Russo, Viviana Bazan
Journal: Journal of Clinical Oncology (2021)

e17551 Background: Ovarian cancer (OC) is the 10 th tumor occurring in women, it accounts for 30% of all malignant tumor affecting female genital tract in Italy. There are several factors that contribute to OC development; in 15-25% of cases family history of breast and ovarian cancer represent the main risk factor. It is well known that pathogenic variants (PVs) occurring in BRCA1/2 genes strongly increase the risk of developing OC, ranging from 50% in BRCA1 PVs carriers to 30% in BRCA2 PVs carriers. Recently genetic polymorphism has been shown to increase cancer risk, consequently polymorphisms in BRCA1/2 genes could represent low penetrance susceptibility alleles and contribute to determine specific clinicopathological features in OC patients harboring BRCA1/2 PVs. Methods: From 2015 to 2021, 338 patients diagnosed with epithelial OC (not mucinous, not borderline) were subjected to BRCA1/2 analysis. After obtaining informed consent, blood samples were processed for genomic DNA isolation; DNA was used for library preparation with the BRaCa Screen kit. Sequencing was performed on the IonS5 platform; variant annotation was performed with Amplicon Suite software. We collected data of both PVs and polymorphisms in BRCA1/2 genes with the aim to evaluate whether a cluster of specific polymorphisms could impact clinicopathological features in BRCA1 PVs carriers. Results: Among the 338 screened EOC, BRCA1/2 PVs were reported in 85 patients (25%). 66% of patients harbored BRCA1 PVs and 34% in BRCA2. The most frequent BRCA1 PVs were the c.4964_4982del (5083del19), c.514delC and c.181T &gt; G; the first and the last are known for their founder effect in Italy and Eastern Europe. Looking at BRCA1 gene, in 75% of patients we identified a polymorphisms cluster (c.2082C &gt; T, c.2311T &gt; C, c.2612C &gt; T, c.3113A &gt; G, c.3548A &gt; G, c.4308T &gt; C, c.4837A &gt; G). The c.514delC and c.181T &gt; G PVs are always associated with the cluster and two additional polymorphisms, the c.2077G &gt; A and the c.1067A &gt; G respectively. Conversely, the cluster seems not to be associated with the PVs 5083del19. Interestingly in BRCA1-5083del19 PV carriers median age at OC diagnosis was 50 years (range 45-69). On average, these patients developed ovarian cancer 6 years earlier than other BRCA1 PV carriers (median age at diagnosis 57 years; range 30-81). Bilateral tumors were frequent and occurred in 57% of the patients versus 33% in OC patients carrying other BRCA1 PVs. Therefore, it seems that the cluster has a “protective” effect and that its absence reduces age at diagnosis. Conclusions: Despite this study has the main limitation of a small sample size, we have reported a possible association between polymorphisms cluster and clinicopathological features in BRCA1 PVs carriers. By further investigating this aspect in a larger cohort, we might be able to prove the role of this cluster in increasing or reducing OC risk and providing clinicians more information useful for patients’ stratification.