Germline investigation in male breast cancer of DNA repair genes by next-generation sequencing

• Published in: Breast cancer research and treatment Vol. 178; no. 3; pp. 557 - 564
• Main Authors: Scarpitta, R., Zanna, I., Aretini, P., Gambino, G., Scatena, C., Mei, B., Ghilli, M., Rossetti, E., Roncella, M., Congregati, C., Bonci, F., Naccarato, A. G., Palli, D., Caligo, M. A.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2019; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; BRCA1 protein; BRCA2 protein; Breast cancer; Breast Neoplasms, Male - blood; Breast Neoplasms, Male - genetics; Breast Neoplasms, Male - pathology; Cancer; Cancer research; Deoxyribonucleic acid; DNA; DNA repair; DNA Repair - genetics; DNA sequencing; ERCC1 protein; Exons; Family; Family medical history; Gene mutations; Genes; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic screening; Genetic Testing; Genetic Variation; Genome, Human - genetics; Genomes; Genomics; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humans; Male; Medicine; Medicine & Public Health; Mens health; Middle Aged; Mutation; Neoplasm Proteins - genetics; Next-generation sequencing; Oncology; Pathogenicity; Pedigree; Preclinical Study; Risk factors; Next-generation sequencing; DNA repair genes; Familial breast cancer; Breast cancer risk in men; Male breast cancer
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-019-05429-z

Purpose
In order to better define the breast cancer (BC) genetic risk factors in men, a germline investigation was carried out on 81 Male BC cases by screening the 24 genes involved in BC predisposition, genome stability maintenance and DNA repair mechanisms by next-generation sequencing.
Methods
Germline DNAs were tested in a custom multi-gene panel focused on all coding exons and exon–intron boundaries of 24 selected genes using two amplicon-based assays on PGM-Ion Torrent (ThermoFisher Scientific) and MiSeq (Illumina) platforms. All variants were recorded and classified by using a custom pipeline.
Results
Clinical pathological data and the family history of 81 Male BC cases were gathered and analysed, revealing the average age of onset to be 61.3 years old and that in 35 cases there was a family history of BC. Our genetic screening allowed us to identify a germline mutation in 22 patients (23%) in 4 genes:
BRCA2
,
BRIP1
,
MUTYH
and
PMS2
. Moreover, 12 variants of unknown clinical significance (VUS) in 9 genes (
BARD1
,
BRCA1
,
BRIP1
,
CHEK2
,
ERCC1
,
NBN
,
PALB2
,
PMS1
,
RAD50
) were predicted as potentially pathogenic by in silico analysis bringing the mutation detection rate up to 40%.
Conclusion
As expected, a positive family history is a strong predictor of germline
BRCA2
mutations in male BC. Understanding the potential pathogenicity of VUS represents an extremely urgent need for the management of BC risk in Male BC cases and their own families.