Abstract 1236: Insight into genetic susceptibility to BRCA-negative male breast cancer by multigene panel testing: Results from a multicenter study in Italy
Authors: Rizzolo Piera , Zelli Veronica , Silvestri Valentina , Valentini Virginia , Spinelli Alessandro , Tibiletti Maria Grazia , Russo Antonio , Varesco Liliana , Giannini Giuseppe , Calistri Daniele , Cortesi Laura , Viel Alessandra , Montagna Marco , Peterlongo Paolo , Radice Paolo , Palli Domenico , Ottini Laura 
Published: August 2018

Abstract
Background: Male breast cancer (MBC) is a rare disease, representing less than 1% of all breast cancers (BC). Although rare, MBC remains a substantial cause for morbidity and mortality in men. MBC etiology appears to be largely associated with genetic factors. Inherited mutations in BRCA2, PALB2 and BRCA1 genes, predispose to MBC and account for about 15% of all cases. Thus, a fraction of MBC cases remains to be assigned to specific genetic factors. Here, we aimed at investigating the genetic component of BRCA1/2 mutation negative MBC cases and at identifying germline mutations that could further explain MBC genetic susceptibility.
Materials and methods: We performed a genomic screening of a well-characterized series of 502 BRCA1/2 mutation negative Italian MBC cases by a comprehensive multi-gene custom panel of 50 cancer-related genes, using MiniSeq platform (Illumina). We also compared the main clinical-pathologic characteristics of MBCs in mutation carriers and non-carriers using Fisher exact test and t-test, where appropriate. All statistical analyses were performed with the R software (www.r-project.org).
Results: Overall 6% of BRCA1/2 mutation negative MBC cases were found to carry a pathogenic variant in the genes analyzed. In particular, PALB2 and ATM were the most frequently altered genes (1.1% and 0.7%, respectively). Mutations in known/proposed BC genes, such as BARD1, BLM, BRIP1, CASP8, CHEK2, FANCM, NBN, NF1, RAD50, RAD51C and RAD51D, as well as in genes considered not closely related to BC predisposition, such as APC, EPCAM and MUTYH, were also identified. Intriguingly, the same NBN mutation was identified in three unrelated MBC cases. Mutation carriers were more likely to have a personal history of cancer in addition to MBC (p=0.0045) and family history of cancer other than breast and ovarian cancer (p=0.0004).
Conclusions: This study may help to gain more insight into the genetic susceptibility of MBC. Our results support the central role of PALB2 in MBC susceptibility, point to a relevant role of ATM and confirm a low impact of CHEK2 mutations on MBC predisposition in the Italian population. Considering that pathogenic mutations were found only in a fraction of the genes analyzed, our data indicate that the identification of the more appropriate genes for the genomic screening of MBC cases is essential in order to develop a comprehensive and specific MBC susceptibility panel with implications for clinical management and counselling of patients and their families. Moreover, our results suggest that multigene testing approach may benefit appropriately selected patients, especially those with a personal or family history of cancer other than breast/ovarian cancer.
Study supported by AIRC (IG 16933) to L.O.
Citation Format: Piera Rizzolo, Veronica Zelli, Valentina Silvestri, Virginia Valentini, Alessandro Spinelli, Maria Grazia Tibiletti, Antonio Russo, Liliana Varesco, Giuseppe Giannini, Daniele Calistri, Laura Cortesi, Alessandra Viel, Marco Montagna, Paolo Peterlongo, Paolo Radice, Domenico Palli, Laura Ottini. Insight into genetic susceptibility to BRCA-negative male breast cancer by multigene panel testing: Results from a multicenter study in Italy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1236.