Molecular Features and Actionable Gene Targets of Testicular Germ Cell Tumors in a Real-World Setting

Molecular profiling of testicular germ cell tumors (TGCTs) provides critical insights into personalized treatment approaches, particularly for patients with recurrent or treatment-resistant disease. In this study, we retrospectively analyzed clinicopathological and targeted genomic sequencing data from 27 TGCT patients, including 7 seminomas, 19 non-seminomas, and 1 prepubertal type teratoma, across stage I (48%), stage II (41%), and stage III (11%). Tumor samples were obtained from 27 orchiectomies, with additional pathological specimens collected from 16 of these patients during retroperitoneal lymph node dissections (RPLNDs); these included 8 chemotherapy-naïve and 8 post-chemotherapy cases. The median tumor mutational burden (TMB) was 0.5 mutations/Mb, consistent with the low mutation rate typically observed in TGCTs. Somatic mutations and copy number gain alterations were detected in 56% (15/27) of patients, primarily in <i>KRAS</i> (25.9%), <i>KIT</i> (11.1%), and <i>PIK3CB</i> (7.4%). PD-L1 positive immunoreactivity by immunohistochemistry was observed in 75% of tumors (60% in stage I, 100% in stage III) analyzed (<i>n</i> = 8), suggesting potential immune checkpoint inhibitor applicability in advanced disease. Microsatellite instability (MSI) status was identified in 23 tumors; all were classified as MSI-low, supporting the rarity of MSI-driven tumorigenesis in TGCTs. Actionable gene alterations linked to FDA-approved therapies, interventional therapies, and clinical trials in TGCTs and other cancers (lung, skin, colon, liver, stomach, and breast) were present in 59.3% (16/27) of patients, indicating potential therapeutic repurposing. Additionally, germline variants of uncertain clinical significance in known cancer actionable genes, including <i>MSH2</i>, <i>MSH6</i>, <i>RB1</i>, and <i>BRCA2</i>, were found in 9 patients, warranting further investigation regarding their clinical relevance and susceptibility risk. Our findings highlight that a substantial proportion of TGCT patients harbor potentially actionable molecular alterations across all disease stages.