Browsing by Subject "Testicular germ cell tumors"

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    Emerging Prognostic Biomarkers in Testicular Germ Cell Tumors: Looking Beyond Established Practice
    (Frontiers, 2018-11-28) Chovanec, Michal; Albany, Constantine; Mego, Michal; Montironi, Rodolfo; Cimadamore, Alessia; Cheng, Liang; Pathology and Laboratory Medicine, School of Medicine
    Testicular germ cell tumors are unique among solid cancers. Historically, this disease was deadly if progressed beyond the stage I. The implementation of cisplatin-based chemotherapy regimens has drastically changed the clinical outcome of metastatic testicular cancer. Several biomarkers were established to refine the prognosis by International Germ Cell Collaborative Group in 1997. Among these, the most significant were primary tumor site; metastatic sites, such as non-pulmonary visceral metastases; and the amplitude of serum tumor markers α-fetoprotein, β-chorionic gonadotropin, and lactate dehydrogenase. Since then, oncology has experienced discoveries of various molecular biomarkers to further refine the prognosis and treatment of malignancies. However, the ability to predict the prognosis and treatment response in germ cell tumors did not improve for many years. Clinical trials with novel targeting agents that were conducted in refractory germ cell tumor patients have proven to have negative outcomes. With the recent advances and developments, novel biomarkers emerge in the field of germ cell tumor oncology. This review article aims to summarize the current knowledge in the research of novel prognostic biomarkers in testicular germ cell tumors.
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    MicroRNA‐371–373 cluster and methylome analysis suggests that a subset of ‘somatic‐type’ malignancies arising in germ cell tumors may originate in yolk sac tumor components
    (Wiley, 2025) Lobo, João; Tavares, Nuno Tiago; Fonseca, Diana; Jerónimo, Carmen; Henrique, Rui; Wyvekens, Nicolas; Yang, Yiying; Snuderl, Matija; Maclean, Fiona; Gordetsky, Jennifer; Fletcher, Christopher D. M.; Hirsch, Michelle S.; Hornick, Jason L.; Idrees, Muhammad T.; Collins, Katrina; Warmke, Laura; Ulbright, Thomas M.; Acosta, Andres M.; Pathology and Laboratory Medicine, School of Medicine
    Somatic-type malignancies (SMs) arising in germ cell tumors (GCTs) are aggressive neoplasms resistant to systemic treatment. Most are diagnosed in metastatic sites after chemotherapy; however, they have also been well-documented in primary testicular GCTs. Historically, SMs were thought to originate in components of teratoma that acquire molecular alterations equivalent to those that characterize their true somatic counterparts. However, recent studies have shown that SMs typically lack the hallmark molecular alterations seen in similar somatic tumors. Additionally, clinicopathologic and molecular data suggest that a subset may derive from yolk sac tumor (YST) rather than teratoma. In this study, we evaluated the relationship between conventional histological types of GCTs and SMs by comparing expression of microRNA (miR)-371-373 and genomic methylation profiles. A total of 96 samples (including multiple paired conventional GCT-SM samples from individual tumors) were assessed for miR-371-373 expression by RT-qPCR and genomic DNA methylation using a clinically validated assay. Expression of miR-371-373 was higher in conventional GCTs than in SMs (considered as a single category encompassing all histological subtypes). However, miR-371-373 expression was heterogeneous among SMs, with significantly higher levels in sarcomatoid YST (SYST) and glandular neoplasms than in other SMs. Genomic DNA methylation analysis showed that SMs (considered as a single category) did not form a distinct cluster. Instead, they grouped into multiple clusters that did not show perfect correspondence with histology and often included conventional GCTs. Genome-wide methylation assessment showed a higher abundance of hypermethylated regions in SMs than in conventional GCTs. Analysis of paired conventional GCT and 'somatic-type' components that did not meet size criteria for SMs dissected from individual tumors demonstrated separation according to histology, suggesting that epigenetic processes play a role in the transition from conventional GCT to 'somatic-type' phenotypes. Gene-level and pathway-level analyses identified MAPK/RAS signaling, mitosis/proliferation, differentiation towards neural tissue/neuroectoderm, epithelial-to-mesenchymal transition, and DNA repair as key differentially regulated processes in components with somatic-type histology, suggesting mechanisms of progression from conventional to 'somatic' phenotypes in GCT. These results support the hypothesis that a subset of SMs derive from YST and suggest that some subtypes (such as SYST) may represent 'intermediate' phenotypes. Additionally, analysis of differentially methylated promoter regions in SM identified genes and biologic processess that may underlie 'somatic tranformation' in GCTs.
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    Targeting of Deregulated Wnt/β-Catenin Signaling by PRI-724 and LGK974 Inhibitors in Germ Cell Tumor Cell Lines
    (MDPI, 2021-04-20) Schmidtova, Silvia; Kalavska, Katarina; Liskova, Veronika; Plava, Jana; Miklikova, Svetlana; Kucerova, Lucia; Matuskova, Miroslava; Rojikova, Lucia; Cierna, Zuzana; Rogozea, Adriana; Konig, Heiko; Albany, Costantine; Mego, Michal; Chovanec, Michal; Medicine, School of Medicine
    The majority of patients with testicular germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. However, for a subset of patients present with cisplatin-refractory disease, which confers a poor prognosis, the treatment options are limited. Novel therapies are therefore urgently needed to improve outcomes in this challenging patient population. It has previously been shown that Wnt/β-catenin signaling is active in GCTs suggesting that its inhibitors LGK974 and PRI-724 may show promise in the management of cisplatin-refractory GCTs. We herein investigated whether LGK-974 and PRI-724 provide a treatment effect in cisplatin-resistant GCT cell lines. Taking a genoproteomic approach and utilizing xenograft models we found the increased level of β-catenin in 2 of 4 cisplatin-resistant (CisR) cell lines (TCam-2 CisR and NCCIT CisR) and the decreased level of β-catenin and cyclin D1 in cisplatin-resistant NTERA-2 CisR cell line. While the effect of treatment with LGK974 was limited or none, the NTERA-2 CisR exhibited the increased sensitivity to PRI-724 in comparison with parental cell line. Furthermore, the pro-apoptotic effect of PRI-724 was documented in all cell lines. Our data strongly suggests that a Wnt/β-catenin signaling is altered in cisplatin-resistant GCT cell lines and the inhibition with PRI-724 is effective in NTERA-2 CisR cells. Further evaluation of Wnt/β-catenin pathway inhibition in GCTs is therefore warranted.