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Clonal Analyses of Refractory Testicular Germ Cell Tumors

ABSTRACT: Clonal Analyses of Refractory Testicular Germ Cell Tumors

PROVIDER: PRJNA508792 | ENA |

REPOSITORIES: ENA

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Clonal Analyses of Refractory Testicular Germ Cell Tumors

Project description:We used DNA content-based flow cytometry to distinguish and isolate nuclei of clonal tumor populations from primary and metastatic refractory testicular germ cell tumors (TGCTs) tissues. We then interrogated each sorted tumor populationwith whole genome aCGH and next generation sequencing (NGS). we have explored the clonal basis of refractory TGCT by investigating distinct tumor populations that were present in each tumor. Notably this included resected primary tissues and treatment refractory metastases that arose after high dose chemotherapy. These results provide new knowledge regarding the role of clonal selection and selected genomic lesions in the resistance to chemotherapy in TGCT within this exceptional cohort.

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Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methlation inhibitor guadecitabine

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Project description:Normal, premalignant and various histological subtypes of testicular germ cell tumor (TGCT) tissues were hybridized against Universal Human Reference RNA (Stratagene) onto Agilent 60mer oligo microarrays (GEO accession no GPL885). In vitro time series of two TGCT cell lines, NTERA2 and 2102Ep, treated with retinoic acid for 0, 3, and 7 days were also included. The data set (30 hybridizations) is particularly useful for comparisons between various histological subtypes of TGCT versus each other or versus normal testis. Keywords = 2102Ep Keywords = Agilent oligo microarrays Keywords = carcinoma in situ Keywords = choriocarcinoma Keywords = development Keywords = developmental biology Keywords = differenciation Keywords = embryogenesis Keywords = embryonal carcinoma Keywords = homo sapiens Keywords = human Keywords = human development Keywords = intratubular germ cell tumor Keywords = nonseminoma Keywords = NTera2 Keywords = pluripotency Keywords = pluripotent Keywords = retinoic acid Keywords = seminoma Keywords = teratocarcinoma Keywords = teratoma Keywords = testis Keywords = testicular germ cell tumor Keywords = testicular neoplasm Keywords = totipotency Keywords = totipotent Keywords = undifferentiated Keywords = universal human reference RNA (Stratagene) Keywords = yolk sac tumor Keywords: other

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Genomic Screening of Testicular Germ Cell Tumors from Monozygotic Twins

Project description:Genomic screening was performed for one family containing MZ twins with testicular germ cell tumors, in order to define alterations associated with risk of tumor development.

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Project description:To investigate the role of the testicular germ cell tumor cells in complex traits, we generated ATAC-seq and Promoter Focused Capture C to gain insight into the gene regulatory arcitecture contacting promoters in an testicular cell line NT2-D1 model of testicular cancer

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microRNA profiling of normal testes and testicular germ cell tumors using deep sequencing approach

Project description:Several observations have pointed a link between small RNA pathway and testicular germ cell tumorigenesis. Yet, the role of small RNAs in testicular germ cell tumors (TGCTs) is still not completely understood. In this study, we characterized the expression profiles of sRNAs in 9 primary sporadic TGCTs and 2 normal testes (NTs) using a sequencing approach. Our data show comprehensive coverage of microRNAs (miRNAs) expressed in human TGCT tissues and NTs, including the identification of 29 candidate novel miRNAs. We identified the differentially expression of miR-506~514 cluster and miR-21, miR-223 in the TGCTs compared to NTs. Functionally, we showed that miR-514a-3p positively regulates apoptosis through directly regulating PEG3. We further demonstrate that PEG3 activates NF-kappa B pathway in human testicular germ cell tumors.

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Genomic Screening of Testicular Germ Cell Tumors from Monozygotic Twins

Project description:Genomic screening was performed for one family containing MZ twins with testicular germ cell tumors, in order to define alterations associated with risk of tumor development. Copy number alterations were evaluated using array-CGH (4x44K, Agilent Technologies) in one seminoma and one embryonal carcinoma (EC) from MZ twins. In addition, genomic alterations from the tumors and peripheral blood cells of the twins were compared to the parental genomes via their peripheral blood cells.

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Project description:Germ cell tumors (GCTs) can be cured with cisplatin-based therapy, although a clinically significant number of patents are refractory and die of progressive disease. Based on preclinical studies indicating that refractory testicular GCTs are hypersensitive to hypomethylating agents (HMA), we conducted a phase I trial [NCT02429466] of the next-generation HMA guadecitabine (SGI-110) in combination with cisplatin in patients with recurrent, cisplatin-resistant GCTs. The primary endpoint was safety and toxicity including DLT and MTD. A total of 14 patients were enrolled. The majority of patients were heavily pretreated. MTD was determined to be 30 mg/m2 guadecitabine followed by cisplatin 100 mg/m2. DLTs were neutropenia and thrombocytopenia. Three patients had partial responses by RECIST criteria, two of these patients qualified as complete responses by serum tumor marker criteria with survival of 16 and 26 months. Three patients also had stable disease for an overall response rate of 23% and clinical benefit rate of 46%. Genome-wide analysis pre- and post-guadecitabine indicated dramatic and widespread global DNA demethylation in cell-free plasma samples including in the promoters of genes of cancer related pathways. In summary, the combination of guadecitabine followed by cisplatin was tolerable and demonstrated biological activity in patients with platinum refractory GCTs.

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