Comprehensive Genomic Profiling through Panel-based and Whole-exome Sequencing in a Population-based Chinese Han Male Breast Cancer Cohort

Purpose The molecular characterization of male breast cancer (MaBC) has long been understudied, primarily due to its rare occurrence. Clinical management of MaBC remains profoundly challenging, with current therapeutic strategies largely extrapolated from female breast cancer protocols. Methods Through panel-based sequencing targeting BRCA1, BRCA2 and PALB2 variants, we delineated the genomic landscape of 96 MaBC cases. Subsequent whole exome sequencing (WES) of 84 BRCA1/2 and PALB2-mutation-negative MaBC patients, compared against 4,480 healthy controls, revealed compelling findings. Results Pathogenic variants in BRCA1/2 and PALB2 were identified in 14.6% (14/96) of MaBC cases, with BRCA2 mutations predominating at 12.5% (n = 12). Notably, one patient harbored the BRCA1 c.4015G > T stop_gained mutation, while another exhibited the PALB2 c.481_482dupGA alteration. Our analysis further uncovered 170 pathogenic/likely-pathogenic mutations and 388 rare variants of uncertain significance (VUS), with RAD50, DMD, ARSA, and ABCC6 demonstrating notable genetic pleiotropy. Conclusion As the inaugural germline genomic investigation of MaBC in a Han Chinese population, this work reveals clinically actionable alterations with diagnostic and therapeutic implications. These discoveries not only advance our understanding of MaBC's molecular architecture but also underscore the critical need for dedicated research into this malignancy.