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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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Clonal analyses of refractory testicular germ cell tumors.

Project description:Testicular germ cell tumors (TGCTs) are unique amongst solid tumors in terms of the high cure rates using chemotherapy for metastatic disease. Nevertheless, TGCTs still kill approximately 400 men per year, at a median age of 30 years, in the United States. This young age of mortality dramatically amplifies the impact of these deaths for the patients and their often young families. Furthermore the high cure rate makes it difficult to conduct further clinical trials of non curable disease. TGCTs are characterized by a marked aneuploidy and the presence of gain of chromosomal region 12p. Genomic testing may offer the ability to identify potentially lethal TGCTs at the time of initial diagnosis. However sequencing based studies have shown a paucity of somatic mutations in TGCT genomes including those that drive refractory disease. Furthermore these studies may be limited by genetic heterogeneity in primary tumors and the evolution of sub populations during disease progression. Herein we applied a systematic approach combining DNA content flow cytometry, whole genome copy number and whole exome sequence analyses to interrogate tumor heterogeneity in primary and metastatic refractory TGCTs. We identified both known and novel somatic copy number aberrations (12p, MDM2, and RHBDD1) and mutations (XRCC2, PIK3CA, RITA1) including candidate markers for platinum resistance that were present in a primary tumor of mixed histology and that remained after tandem autologous stem cell transplant.

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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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