Genomic landscape and homologous recombination deficiency in malignant germ cell tumors reveals sex‐specific therapeutic opportunities

Malignant germ cell tumors (GCTs) are relatively rare tumors with limited therapeutic options. This study examined the homologous recombination deficiency (HRD) status and genomic characteristics in 14 patients with GCT who underwent next-generation sequencing. HRD was evaluated using the genomic instability score (GIS), which incorporates three components: loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transition (LST). Our findings showed that 57.1% (8/14) of participants were HRD positive. Female patients presented a significantly higher prevalence of HRD positivity (87.5%, 7/8) compared with male patients (16.7%, 1/6). HRD positivity in female cases had a mean GIS of 56 (range 48-76), including one patient harboring a germline BRCA2 p.S2670L (c.8009C>T) likely pathogenic mutation. LST demonstrated the strongest correlation with the integrated GIS (R² = 0.945), followed by LOH (R² = 0.872). Distinct mutation patterns were observed based on gender. GCTs in male cases predominantly exhibited mutations in TP53 (50% in yolk sac tumors; 50% in teratomas). GCTs in male cases also demonstrated TP53 mutations in one mediastinal yolk sac tumor and one mediastinal teratoma. Male cases showed recurrent alterations in KRAS, PRKDC, and CDKN1B, alongside frequent chromosome 12p amplifications in two cases. One particularly complex mediastinal teratoma in a male patient, featuring rhabdomyosarcomatous transformation, displayed bidirectional intergenic (TWSG1, MANEA-DT)-ROS1fusions, a HRAS-intergenic (RNH1) fusion, and MET focal amplification. These findings suggest a promising therapeutic opportunity with poly (ADP-ribose) polymerase (PARP) inhibitors for female patients with HRD-positive GCTs. Additionally, the complex composition of gene variants found in male patients with GCTs, including ROS1 fusions and MET focal amplification, points toward potential targeted therapeutic strategies. This study underscores the presence of sex-specific therapeutic vulnerabilities in GCTs, which warrant further exploration in larger cohorts. © 2026 The Pathological Society of Great Britain and Ireland.