Genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancer

Purpose

To understand the broader genetic landscape of male breast cancer (MBC), focusing on the utility of genome sequencing (GS) beyond BRCA1/2 (HGNC: 1100, 1101) variants.

Methods

Twenty-four patients with MBC underwent a multistep genetic analysis. Initial screening targeted BRCA1/2 variants followed by GS to identify pathogenic/likely pathogenic germline variants through a 3-tiered classification. Polygenic risk score analysis was further incorporated using a model for female breast cancer with 2666 noncancer controls. Exome sequencing was used to transition from germline to somatic investigations, assessing second-hit variant and mutational signatures.

Results

The GS analysis unveiled previously unrecognized pathogenic/likely pathogenic germline variants in BARD1, ATR, BRIP1, and CHEK2 (HGNC: 952, 882, 20473, 16627) among 21 BRCA1/2-negative patients with MBC, elevating the diagnostic yield from 12.5% to 33.0% in all MBC. Elevated average polygenic risk score was noted compared with controls, with a significant correlation to early-onset MBC when combined with high-penetrance germline pathogenic variants (P = 1.10 × 10⁻⁴). Exome sequencing analysis further identified significant somatic oncogenic drivers and revealed a dominant mutational signature SBS3 across BRCA1/2-negative samples, reinforcing the contribution of omologous recombination deficiency underlying the MBC development.

Conclusion

Our findings extended the MBC genetic spectrum beyond BRCA1/2 and highlighted the intricate interplay of monogenic and polygenic predispositions, presenting a comprehensive MBC genomic profile.