Exome sequencing in BRCA1-2 candidate familias: the contribution of other cancer susceptibility genes

Gabriella Doddato; Floriana Valentino; Annarita Giliberti; Filomena Tiziana Papa; Rossella Tita; Lucia Pia Bruno; Sara Resciniti; Chiara Fallerini; Elisa Benetti; Maria Palmieri; Maria Antonietta Mencarelli; Alessandra Fabbiani; Mirella Bruttini; Alfredo Orrico; Margherita Baldassarri; Francesca Fava; Diego Lopergolo; Caterina Lo Rizzo; Vittoria Lamacchia; Sara Mannucci; Anna Maria Pinto; Aurora Curr; Virginia Mancini; Oncologic Multidisciplinary Team, Azienda Ospedaliera Universitaria Senese; Oncologic Multidisciplinary Team, Azienda Usl Toscana Sud Est; Francesca Mari; Alessandra Renieri; Francesca Ariani

doi:10.3389/fonc.2021.649435

Exome sequencing in BRCA1-2 candidate familias: the contribution of other cancer susceptibility genes

Front Oncol. 2021 May 7:11:649435. doi: 10.3389/fonc.2021.649435. eCollection 2021.

Authors

Gabriella Doddato^{1

2}, Floriana Valentino^{1

2}, Annarita Giliberti^{1

2}, Filomena Tiziana Papa^{1

2}, Rossella Tita³, Lucia Pia Bruno^{1

2}, Sara Resciniti^{1

2}, Chiara Fallerini^{1

2}, Elisa Benetti², Maria Palmieri^{1

2}, Maria Antonietta Mencarelli³, Alessandra Fabbiani^{1

2

3}, Mirella Bruttini^{1

3}, Alfredo Orrico⁴, Margherita Baldassarri^{1

2}, Francesca Fava^{1

2

3}, Diego Lopergolo^{1

2

3}, Caterina Lo Rizzo³, Vittoria Lamacchia^{1

2

3}, Sara Mannucci^{1

2

3}, Anna Maria Pinto³, Aurora Curr^{1

2

3}, Virginia Mancini⁵; Oncologic Multidisciplinary Team, Azienda Ospedaliera Universitaria Senese; Oncologic Multidisciplinary Team, Azienda Usl Toscana Sud Est; Francesca Mari^{1

2

3}, Alessandra Renieri^{1

2

3}, Francesca Ariani^{1

2

3}

Collaborators

Alessandro Neri, Donato Casella, Andrea Bernini, Stefania Marsili, Roberto Petrioli, Salvatora Tindara Miano, Alessandra Pascucci, Ignazio Martellucci, Monica Crociani, Marta Vannini, Federica Fantozzi, Andrea Stella, Alessia Carmela Tripodi, Angelamaria Giusti, Alfonso Fausto, Lucia Mantovani, Francesca Belardi, Angelo Martignetti, Amalia Falzetta, Camilla Casi, Paolo Petreni, Beatrice Forzoni, Enrico Tucci, Tiziana Baglioni, Luciana Biscari, Antonia Borgomastro, Pamela Torre, Francesco Di Clemente, Simona Scali, Marianna Turrini, Maria Deligianni, Sabrina Del Buono, Simonetta Magnanini, Alice Baldi, Tommaso Amato, Ulpjana Gjondedaj, Giorgio Bastreghi, Giovanni Angiolucci, Carmelo Bengala, Roberta Di Rocco

Affiliations

¹ Medical Genetics, University of Siena, Siena, Italy.
² Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy.
³ Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
⁴ Molecular Diagnosis and Characterization of Pathogenic Mechanisms of Rare Genetic Diseases, Azienda Ospedaliera Universitaria Senese and Clinical Genetics, ASL Toscana SudEst. Ospedale della Misericordia, Grosseto, Italy.
⁵ Unit of Pathology, Department of Medical Biotechnology, University of Siena, Siena, Italy.

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 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 BRCA1-2) 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 to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer (ATM, BRIP1, CDH1, PALB2, PTEN, RAD51C, and TP53) (5% diagnostic yield) and 11 in candidate 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 candidate non-canonical genes.

Keywords: BRCA1; BRCA2; cancer susceptibility genes; HBOC, ES (Excome Sequencing).

Copyright 2021 Doddato, Valentino, Giliberti, Papa, Tita, Bruno, Resciniti, Fallerini, Benetti, Palmieri, Mencarelli, Fabbiani, Bruttini, Orrico, Baldassarri, Fava, Lopergolo, Lo Rizzo, Lamacchia, Mannucci, Pinto, Curr, Mancini, Oncologic Multidisciplinary Team, Azienda Ospedaliera Universitaria Senese, Oncologic Multidisciplinary Team, Azienda Usl Toscana Sud Est, Mari, Renieri and Ariani.