Whole-Genome Sequencing Analysis of Male Breast Cancer Unveils Novel Structural Events and Potential Therapeutic Targets.
Academic Article
Overview
abstract
The molecular characterization of male breast cancer (MaBC) has received limited attention in research, mostly due to its low incidence rate, accounting for only 0.5-1% of all reported cases of breast cancer each year. Managing MaBC presents significant challenges, with most treatment protocols being adapted from those developed for female breast cancer. Utilizing whole-genome sequencing (WGS) and state-of-the-art analyses, the genomic features of ten (n=10) MaBC cases were delineated and correlated with clinical and histopathological characteristics. Using fluorescence in situ hybridization (FISH), an additional cohort of 18 patients was interrogated to supplement WGS findings. The genomic landscape of MaBC uncovered significant genetic alterations that could influence diagnosis and treatment. We found common somatic mutations in key driver genes such as FAT1, GATA3, SMARCA4, and ARID2. Our study also mapped out structural variants (SVs) that impact cancer-associated genes like ARID1A, ESR1, GATA3, NTRK1, and NF1. Using a WGS-based classifier, homologous recombination deficiency (HRD) was identified in two cases, both presenting with deleterious variants in BRCA2. Noteworthy was the observation of FGFR1 amplification in 21% of cases. Altogether, we identified at least one potential therapeutic target in 8 of 10 cases, including high tumor mutational burden, FGFR1 amplification and HRD. Our study is the first WGS characterization of MaBC, which uncovered potentially relevant variants including structural events in cancer genes, HRD signatures, and germline pathogenic mutations. Our results demonstrate unique genetic markers and potential treatment targets in MaBC, thereby underlining the necessity of tailoring treatment strategies for this under-studied patient population. These WGS-based findings add to the growing knowledge of MaBC genomics and highlight the need to expand research on this type of cancer.
