scholarly journals The Role of TP53 in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors

2021 ◽  
Vol 22 (21) ◽  
pp. 11774
Author(s):  
Dennis M. Timmerman ◽  
Thomas F. Eleveld ◽  
Ad J. M. Gillis ◽  
Carlijn C. Friedrichs ◽  
Sanne Hillenius ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cell Line ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors ◽  
Underlying Mechanism ◽  
Potential Candidate ◽  
Knock Out ◽  
Tp53 Mutations ◽  
Platinum Based Chemotherapy

Germ cell tumors (GCTs) are considered to be highly curable; however, there are major differences in the outcomes related to histology and anatomical localization. GCTs originating from the testis are, overall, sensitive to platinum-based chemotherapy, whereas GCTs originating from the mediastinum show a worse response, which remains largely unexplained. Here, we address the differences among GCTs from two different anatomical locations (testicular versus mediastinal/extragonadal), with a specific focus on the role of the P53 pathway. It was recently shown that GCTs with TP53 mutations most often localize to the mediastinum. To elucidate the underlying mechanism, TP53 knock-out lines were generated in cisplatin-sensitive and -resistant clones of the representative 2102Ep cell line (wild-type TP53 testicular GCT) and NCCIT cell line (hemizygously mutated TP53, mutant TP53 mediastinal GCT). The full knock-out of TP53 in 2102Ep and resistant NCCIT resulted in an increase in cisplatin resistance, suggesting a contributing role for P53, even in NCCIT, in which P53 had been reported to be non-functional. In conclusion, these results suggest that TP53 mutations contribute to the cisplatin-resistant phenotype of mediastinal GCTs and, therefore, are a potential candidate for targeted treatment. This knowledge provides a novel model system to elucidate the underlying mechanism of clinical behavior and possible alternative treatment of the TP53 mutant and mediastinal GCTs.

scholarly journals Surgical controversies in the management of post-chemotherapy nonretroperitoneal residual disease in metastatic nonseminomatous germ cell tumors

2016 ◽  
Vol 05 (01) ◽  
pp. 20-22 ◽  
Author(s):  
Durgatosh Pandey ◽  
Pankaj Kumar Garg ◽  
Mukur Dipi Ray ◽  
Ashutosh Mishra
Keyword(s):  
Germ Cell ◽  
Residual Disease ◽  
Histopathological Examination ◽  
Germ Cell Tumors ◽  
Surgical Excision ◽  
Adjunct Treatment ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Nonseminomatous Germ Cell Tumors

AbstractFollowing the advent of platinum-based chemotherapy, Surgery, excepting orchidectomy, has become an adjunct treatment in the management of metastatic non-seminomatous germ cell tumors (NSGCT). Role of surgery comes into play in metastatic NSGCT when residual disease persists following standard chemotherapy. Surgical excision of all post chemotherapy residual disease at all places, whenever surgically feasible with acceptable morbidity and mortality, should be undertaken. As histopathological examination of the excised postchemotherapy residue shows only necrosis and fibrosis in significant number of patients; surgical exercise in this group of patients seems futile and unwarranted retrospectively. This issue becomes more contentious when surgeons are confronted with multiple nonretroperitoneal post chemotherapy residues. This article aims to deal with the management of postchemotherapy nonretroperitoneal residues in metastatic NSGCT.

scholarly journals TEX13B is important for germ cell development and male fertility

2022 ◽  
Author(s):  
Umesh Kumar ◽  
Digumarthi V S Sudhakar ◽  
Nithyapriya Kumar ◽  
Hanuman T Kale ◽  
Rajan Kumar Jha ◽  
...  
Keyword(s):  
Male Infertility ◽  
Germ Cell ◽  
Cell Line ◽  
Germ Cells ◽  
Male Partner ◽  
Epidemiological Studies ◽  
Reproductive Age ◽  
Sequencing Data ◽  
Knock Out

AbstractThe recent epidemiological studies suggest that nearly one out of every 7 reproductive age couples face problem to conceive a child after trying for at least one year. Impaired fertility of the male partner is causative in approximately 50% of the infertile couples. However, the etiologies of large proportion of male infertility are still unclear. Our unpublished exome sequencing data identified several novel genes including TEX13B, which motivated us to further explore the role of TEX13B in male infertility in large infertile case control cohort. Hence in this study, we have examined the role of TEX13B in male infertility by whole gene sequencing 628 infertile and 427 control men and have demonstrated the functional role of Tex13b in spermatogonia GC1spg (GC1) cells. We identified 2 variants on TEX13B which are tightly associated with male infertility. TEX13B gene exclusively expressed in germ cells, but its molecular functions in germ cells are still unknown. Hence, we demonstrated the functional importance of Tex13b in GC1 cell line by genomic manipulation via CRISPR-Cas9 and mass spectrometry-based whole cell proteomics. The gene knock out in GC1 cell line clearly shows that Tex13b play an important role in germ cell growth and morphology. We demonstrate that Tex13b knockout or conditional overexpression in GC1 cells reprograms the metabolic status from an oxidative phosphorylation to glycolysis state and vice versa. In conclusion, our study clearly showed the importance of Tex13b in germ cells development and Its association with male infertility.

Molecular Mechanisms of Resistance in Testicular Germ Cell Tumors - clinical Implications

2018 ◽  
Vol 18 (10) ◽  
pp. 967-978 ◽  
Author(s):  
Katarina Kalavska ◽  
Vincenza Conteduca ◽  
Ugo De Giorgi ◽  
Michal Mego
Keyword(s):  
Germ Cell ◽  
Molecular Mechanisms ◽  
Cisplatin Resistance ◽  
Apoptotic Cell ◽  
Germ Cell Tumors ◽  
Treatment Resistance ◽  
Experimental Models ◽  
Testicular Germ Cell Tumors ◽  
Testicular Germ Cell ◽  
Repair Capacity

Testicular germ cell tumors (TGCTs) represent the most common malignancy in men aged 15-35. Due to these tumors’ biological and clinical characteristics, they can serve as an appropriate system for studying molecular mechanisms associated with cisplatin-based treatment resistance. This review describes treatment resistance from clinical and molecular viewpoints. Cisplatin resistance is determined by various biological mechanisms, including the modulation of the DNA repair capacity of cancer cells, alterations to apoptotic cell death pathways, deregulation of gene expression pathways, epigenetic alterations and insufficient DNA binding. Moreover, this review describes TGCTs as a model system that enables the study of the cellular features of cancer stem cells in metastatic process and describes experimental models that can be used to study treatment resistance in TGCTs. All of the abovementioned aspects may help to elucidate the molecular mechanisms underlying cisplatin resistance and may help to identify promising new therapeutic targets.

scholarly journals GCT-06. DIAGNOSIS OF A RARE CASE OF RECURRENT GERM CELL TUMOR BY CSF PLACENTAL ALKALINE PHOSPHATASE PRESENTING WITH DIFFUSE INTRAAXIAL ABNORMALITY IN THE LOWER BRAINSTEM

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii329-iii329
Author(s):  
Hiroki Yamada ◽  
Tomohiro Abiko ◽  
Hirokazu Fujiwara ◽  
Kazunari Yoshida ◽  
Hikaru Sasaki
Keyword(s):  
Alkaline Phosphatase ◽  
Germ Cell ◽  
Germ Cell Tumor ◽  
Rare Case ◽  
Cervical Spinal Cord ◽  
Germ Cell Tumors ◽  
Cell Tumor ◽  
Placental Alkaline Phosphatase ◽  
Steroid Pulse ◽  
Platinum Based Chemotherapy

Abstract INTRODUCTION Germ cell tumors in the central nervous system (CNS) typically arise either at suprasellar and/or pineal region, and occasionally at basal ganglia. We report a case of diagnostically challenging, recurrent germ cell tumor presented with diffuse intraaxial abnormality in and across the lower brainstem, which was diagnosed by the elevated placental alkaline phosphatase (PLAP) level in cerebrospinal fluid (CSF). CASE DESCRIPTION: A 28-year-old man had been treated by chemoradiotherapy at the previous hospital for bifocal suprasellar and pineal lesions with the provisional diagnosis of germinoma without histological confirmation. Three years later, he presented with progressive weakness of bilateral extremities for weeks. Magnetic resonance imaging showed a diffuse, bilaterally symmetric high intensity lesion on T2-weighted image with slight contrast enhancement across the ventral side of the medulla oblongata to the upper cervical spinal cord. Serum and CSF hCG, hCG-β, and AFP were all negative. Since the image findings were atypical for recurrent germ cell tumor, some kind of myelitis was initially suspected. Therefore, steroid pulse therapy was administered. However, the patient’s symptom was still gradually progressing. Then, the CSF PLAP turned out to be positive, indicating the recurrence of germinoma. Accordingly, platinum-based chemotherapy was administered, and the imaging findings, patient’s symptoms, and CSF PLAP began to improve. The patient is to be treated with radiotherapy following chemotherapy. CONCLUSION We report a rare case of CNS germ cell tumor that presented with diffuse intraaxial lesion in the lower brainstem in which examination of CSF PLAP was extremely useful.

scholarly journals The role of staging and adjuvant chemotherapy in stage I malignant ovarian germ cell tumors (MOGTs): the MITO-9 study

2017 ◽  
Vol 28 (2) ◽  
pp. 333-338 ◽  
Author(s):  
G. Mangili ◽  
C. Sigismondi ◽  
D. Lorusso ◽  
G. Cormio ◽  
M. Candiani ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Germ Cell ◽  
Germ Cell Tumors ◽  
Stage I

The role of [18F] FDG-PET, CT/MRI and tumor marker kinetics in the evaluation of postchemotherapy residual masses in metastatic germ cell tumors?prospects for management

2004 ◽  
Vol 22 (2) ◽  
Author(s):  
AnnaC. Pfannenberg ◽  
Karin Oechsle ◽  
Carsten Bokemeyer ◽  
Christian Kollmannsberger ◽  
BernhardM. Dohmen ◽  
...  
Keyword(s):  
Germ Cell ◽  
Tumor Marker ◽  
Fdg Pet ◽  
Germ Cell Tumors ◽  
Pet Ct ◽  
Residual Masses ◽  
18F Fdg ◽  
Fdg Pet Ct

scholarly journals MP81-15 GENETIC BASIS FOR CISPLATIN RESISTANCE IN PATIENTS WITH ADVANCED GERM CELL TUMORS (GCT)

2016 ◽  
Vol 195 (4S) ◽  
Author(s):  
Aditya Bagrodia ◽  
Byron Lee ◽  
William Lee ◽  
Eugene Cha ◽  
John Sfakianos ◽  
...  
Keyword(s):  
Germ Cell ◽  
Genetic Basis ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors

Microsatellite Instability, Mismatch Repair Deficiency, and BRAF Mutation in Treatment-Resistant Germ Cell Tumors

2009 ◽  
Vol 27 (13) ◽  
pp. 2129-2136 ◽  
Author(s):  
Friedemann Honecker ◽  
Hendrik Wermann ◽  
Frank Mayer ◽  
Ad J.M. Gillis ◽  
Hans Stoop ◽  
...  
Keyword(s):  
Germ Cell ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Braf Mutation ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors ◽  
Braf V600e ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Mmr Deficiency

Purpose Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are associated with cisplatin resistance in human germ cell tumors (GCTs). BRAF mutation (V600E) is found in MSI colorectal cancers. The role of RAS/RAF pathway mutations in GCT treatment response is unknown. Patients and Methods Two patient cohorts were investigated: 100 control GCTs (50 seminomas and 50 nonseminomas) and 35 cisplatin-based chemotherapy-resistant GCTs. MMR proteins were analyzed by immunohistochemistry, and eight microsatellite loci were examined for MSI. Tumors were assessed for specific BRAF and KRAS mutations. Results Resistant tumors showed a higher incidence of MSI than controls: 26% versus 0% in two or more loci (P < .0001). All resistant tumors were wild-type KRAS, and two controls (2%) contained a KRAS mutation. There was a significantly higher incidence of BRAF V600E mutation in resistant tumors compared with controls: 26% versus 1% (P < .0001). BRAF mutations were highly correlated with MSI (P = .006), and MSI and mutated BRAF were correlated with weak or absent staining for hMLH1 (P = .017 and P = .008). Low or absent staining of hMLH1 was correlated with promoter hypermethylation (P < .001). Tumors lacking expression of hMLH1 or MSH6 were significantly more frequent in resistant GCTs than in controls (P = .001 and 0.0036, respectively). Within the subgroup of resistant tumors, patients with MSI showed a trend to longer progression-free survival (P = .068). Conclusion We report for the first time a correlation between a gene mutation—BRAF V600E—and cisplatin resistance in nonseminomatous GCTs. Furthermore, a correlation between MMR deficiency, MSI, and treatment failure is confirmed.

scholarly journals Epigenetic Remodeling through Downregulation of Polycomb Repressive Complex 2 Mediates Chemotherapy Resistance in Testicular Germ Cell Tumors

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 796 ◽  
Author(s):  
Ratnakar Singh ◽  
Zeeshan Fazal ◽  
Andrea K. Corbet ◽  
Emmanuel Bikorimana ◽  
Jennifer C. Rodriguez ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors ◽  
Parental Origin ◽  
Testicular Germ Cell Tumors ◽  
Polycomb Repressive Complex ◽  
Testicular Germ Cell ◽  
Polycomb Repressive Complex 2 ◽  
H3k27 Methylation ◽  
Resistant Cells

A greater understanding of the hypersensitivity and curability of testicular germ cell tumors (TGCTs) has the potential to inform strategies to sensitize other solid tumors to conventional chemotherapies. The mechanisms of cisplatin hypersensitivity and resistance in embryonal carcinoma (EC), the stem cells of TGCTs, remain largely undefined. To study the mechanisms of cisplatin resistance we generated a large panel of independently derived, acquired resistant clones from three distinct parental EC models employing a protocol designed to match standard of care regimens of TGCT patients. Transcriptomics revealed highly significant expression changes shared between resistant cells regardless of their parental origin. This was dominated by a highly significant enrichment of genes normally repressed by H3K27 methylation and the polycomb repressive complex 2 (PRC2) which correlated with a substantial decrease in global H3K27me3, H2AK119 ubiquitination, and expression of BMI1. Importantly, repression of H3K27 methylation with the EZH2 inhibitor GSK-126 conferred cisplatin resistance to parental cells while induction of H3K27 methylation with the histone lysine demethylase inhibitor GSK-J4 resulted in increased cisplatin sensitivity to resistant cells. A gene signature based on H3K27me gene enrichment was associated with an increased rate of recurrent/progressive disease in testicular cancer patients. Our data indicates that repression of H3K27 methylation is a mechanism of cisplatin acquired resistance in TGCTs and that restoration of PRC2 complex function is a viable approach to overcome treatment failure.

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