AUTHOR=Doddato Gabriella , Valentino Floriana , Giliberti Annarita , Papa Filomena Tiziana , Tita Rossella , Bruno Lucia Pia , Resciniti Sara , Fallerini Chiara , Benetti Elisa , Palmieri Maria , Mencarelli Maria Antonietta , Fabbiani Alessandra , Bruttini Mirella , Orrico Alfredo , Baldassarri Margherita , Fava Francesca , Lopergolo Diego , Lo Rizzo Caterina , Lamacchia Vittoria , Mannucci Sara , Pinto Anna Maria , Currò Aurora , Mancini Virginia ,  Oncologic Multidisciplinary Team, Azienda Ospedaliera Universitaria Senese ,  Oncologic Multidisciplinary Team, Azienda Usl Toscana Sud Est , Mari Francesca , Renieri Alessandra , Ariani Francesca , Neri Alessandro , Casella Donato , Bernini Andrea , Marsili Stefania , Petrioli Roberto , Miano Salvatora Tindara , Pascucci Alessandra , Martellucci Ignazio , Crociani Monica , Vannini Marta , Fantozzi Federica , Stella Andrea , Tripodi Alessia Carmela , Giusti Angelamaria , Fausto Alfonso , Mantovani Lucia , Belardi Francesca , Martignetti Angelo , Falzetta Amalia , Casi Camilla , Petreni Paolo , Forzoni Beatrice , Tucci Enrico , Baglioni Tiziana , Biscari Luciana , Borgomastro Antonia , Torre Pamela , Di Clemente Francesco , Scali Simona , Turrini Marianna , Deligianni Maria , Del Buono Sabrina , Magnanini Simonetta , Baldi Alice , Amato Tommaso , Gjondedaj Ulpjana , Bastreghi Giorgio , Angiolucci Giovanni , Bengala Carmelo , Di Rocco Roberta 

TITLE=Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes

JOURNAL=Frontiers in Oncology

VOLUME=Volume 11 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.649435

DOI=10.3389/fonc.2021.649435

ISSN=2234-943X

ABSTRACT=Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast and ovarian cancer is higher than in the general population. The prevalent pathogenesis is attributable to inactivating variants of the BRCA1/2 highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Whole Exome Sequencing (WES) we analyzed a series of 200 individuals selected for genetic testing in BRCA1/2 genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large BRCA1/2 deletions/duplications. Focusing on BRCA1/2 genes, data analysis identified 11 cases with pathogenic variants (4 in BRCA1 and 7 in BRCA2) and 12 with uncertain variants (7 in BRCA1 and 5 in BRCA2). Only one case was found with a large BRCA1 deletion. Whole exome analysis allowed us to characterize pathogenic variants in additional causative genes and make the diagnosis in 21 individuals (11% diagnostic yield): 10 with pathogenic variants in genes more traditionally associated to breast and ovarian cancer (ATM, BRIP1, CDH1, PALB2, PTEN, RAD51C and TP53) and 11 in other cancer susceptibility genes (DPYD, ERBB3, ERCC2, MUTYH, NQO2, NTHL1, PARK2, RAD54L and RNASEL). In conclusion, this study allowed a personalized risk assessment and clinical surveillance in an increased number of HBOC families and to broaden the spectrum of causative variants also to “non-canonical” genes.