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=11

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=<p>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 <italic>BRCA1-2</italic> highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Exome Sequencing (ES) we analyzed a series of 200 individuals selected for genetic testing in <italic>BRCA1-2</italic> genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large <italic>BRCA1-2</italic> deletions/duplications. Focusing on <italic>BRCA1-2</italic> genes, data analysis identified 11 cases with pathogenic variants (4 in <italic>BRCA1</italic> and 7 in <italic>BRCA1-2</italic>) and 12 with uncertain variants (7 in <italic>BRCA1</italic> and 5 in <italic>BRCA2</italic>). Only one case was found with a large <italic>BRCA1</italic> deletion. Exome analysis allowed to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer (<italic>ATM</italic>, <italic>BRIP1</italic>, <italic>CDH1</italic>, <italic>PALB2</italic>, <italic>PTEN</italic>, <italic>RAD51C</italic>, and <italic>TP53</italic>) (5% diagnostic yield) and 11 in candidate cancer susceptibility genes (<italic>DPYD</italic>, <italic>ERBB3</italic>, <italic>ERCC2</italic>, <italic>MUTYH</italic>, <italic>NQO2</italic>, <italic>NTHL1</italic>, <italic>PARK2</italic>, <italic>RAD54L</italic>, and <italic>RNASEL</italic>). 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 candidate “non-canonical” genes.</p>