Morales-Grimany Rafael, Giannikou Krinio, Delgado Cesar, Pandit Kshitij, Baky Fady, Amini Armon, Yuen Kit, Gerald Thomas, Badia Rohit, Taylor Jacob, Wang Luke, Javier-Desloges Juan, Margulis Vitaly, Woldu Solomon, Salmasi Amirali, Millard Fred, Mckay Rana R, Bagrodia Aditya
Department of Medicine, School of Medicine, Universidad Central del Caribe, Bayamon, PR 00956, USA.
Department of Urology, Moores Cancer Center, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Int J Mol Sci. 2025 Sep 15;26(18):8963. doi: 10.3390/ijms26188963.
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 (25.9%), (11.1%), and (7.4%). PD-L1 positive immunoreactivity by immunohistochemistry was observed in 75% of tumors (60% in stage I, 100% in stage III) analyzed ( = 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 , , , and , 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.
睾丸生殖细胞肿瘤（TGCT）的分子特征分析为个性化治疗方法提供了关键见解，特别是对于复发或难治性疾病患者。在本研究中，我们回顾性分析了27例TGCT患者的临床病理和靶向基因组测序数据，包括7例精原细胞瘤、19例非精原细胞瘤和1例青春期前型畸胎瘤，涵盖I期（48%）、II期（41%）和III期（11%）。肿瘤样本取自27例睾丸切除术，其中16例患者在腹膜后淋巴结清扫术（RPLND）期间还收集了额外的病理标本；这些标本包括8例未接受过化疗的病例和8例化疗后的病例。肿瘤突变负荷（TMB）中位数为0.5个突变/Mb，与TGCT中通常观察到的低突变率一致。56%（15/27）的患者检测到体细胞突变和拷贝数增加改变，主要发生在（25.9%）、（11.1%）和（7.4%）。在分析的8例肿瘤中，75%观察到通过免疫组织化学检测的PD-L1阳性免疫反应（I期为60%，III期为100%），提示晚期疾病中潜在的免疫检查点抑制剂适用性。在23个肿瘤中确定了微卫星不稳定性（MSI）状态；所有肿瘤均分类为MSI低，支持TGCT中MSI驱动肿瘤发生的罕见性。59.3%（16/27）的患者存在与FDA批准的疗法、介入性疗法以及TGCT和其他癌症（肺癌、皮肤癌、结肠癌、肝癌、胃癌和乳腺癌）临床试验相关的可操作基因改变，表明可能有治疗方法的重新利用。此外，在9例患者中发现了已知癌症可操作基因中临床意义不确定的种系变异，包括、、和，需要进一步研究它们的临床相关性和易感性风险。我们的研究结果强调，相当一部分TGCT患者在所有疾病阶段都存在潜在的可操作分子改变。
