Elucidating human male germ cell development by studying germ cell cancer

Nettersheim, Daniel; Jostes, Sina; Schneider, Simon; Schorle, Hubert

doi:10.1530/rep-16-0114

Cited by 13 publications

(12 citation statements)

References 138 publications

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“…After the WHO classification in 2016, an immunohistochemical study, in 2017, showed that precursor lesions for TGCT had a seminomatous immunophenotype [ 10 ]. The Genome Cancer Atlas (TGCA) project, in 2018, found that TGCT did not have mandatory somatic mutations [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Meta-Analysis of Gene Expressions in Testicular Germ Cell Tumor Histologies

Eyben

Parraga-Alava

2020

IJMS

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There is no consensus as to how a precursor lesion, germ cell neoplasia in situ (GCNIS), develops into the histologic types of testicular germ cell tumor type II (TGCT). The present meta-analysis examined RNA expressions of 24 candidate genes in three datasets. They included 203 samples of normal testis (NT) and histologic types of TGCT. The Fisher’s test for combined p values was used for meta-analysis of the RNA expressions in the three datasets. The histologic types differed in RNA expression of PRAME, KIT, SOX17, NANOG, KLF4, POU5F1, RB1, DNMT3B, and LIN28A (p < 0.01). The histologic types had concordant differences in RNA expression of the genes in the three datasets. Eight genes had overlap with a high RNA expression in at least two histologic types. In contrast, only seminoma (SE) had a high RNA expression of KLF4 and only embryonal carcinoma (EC) had a high RNA expression of DNMT3B. In conclusion, the meta-analysis showed that the development of the histologic types of TGCT was driven by changes in RNA expression of candidate genes. According to the RNA expressions of the ten genes, TGCT develops from NT over GCNIS, SE, EC, to the differentiated types of TGCT.

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Section: Introductionmentioning

confidence: 99%

Meta-Analysis of Gene Expressions in Testicular Germ Cell Tumor Histologies

Eyben

Parraga-Alava

2020

IJMS

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“…Similar to seminoma and embryonal carcinoma, these cells are uniformly positive for the embryonic stem cell marker OCT4/POU5F1, and these cells are typical of the embryonal carcinoma cells isolated from experimentally induced teratocarcinomas. Germ cell neoplasias account for about 4% of all childhood tumors [ 177 , 178 ].…”

Section: Geminin and Germ Cell Neoplasiasmentioning

confidence: 99%

Links between DNA Replication, Stem Cells and Cancer

Vassilev

DePamphilis

2017

Genes

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Cancers can be categorized into two groups: those whose frequency increases with age, and those resulting from errors during mammalian development. The first group is linked to DNA replication through the accumulation of genetic mutations that occur during proliferation of developmentally acquired stem cells that give rise to and maintain tissues and organs. These mutations, which result from DNA replication errors as well as environmental insults, fall into two categories; cancer driver mutations that initiate carcinogenesis and genome destabilizing mutations that promote aneuploidy through excess genome duplication and chromatid missegregation. Increased genome instability results in accelerated clonal evolution leading to the appearance of more aggressive clones with increased drug resistance. The second group of cancers, termed germ cell neoplasia, results from the mislocation of pluripotent stem cells during early development. During normal development, pluripotent stem cells that originate in early embryos give rise to all of the cell lineages in the embryo and adult, but when they mislocate to ectopic sites, they produce tumors. Remarkably, pluripotent stem cells, like many cancer cells, depend on the Geminin protein to prevent excess DNA replication from triggering DNA damage-dependent apoptosis. This link between the control of DNA replication during early development and germ cell neoplasia reveals Geminin as a potential chemotherapeutic target in the eradication of cancer progenitor cells.

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“…Seminomas retain to the most part the genetic and epigenetic signature of PGCs i.e. they express pluripotency (LIN28, NANOG, POU5F1 (OCT4)) and PGC (PRDM1, TFAP2C, DMRT1, cKIT, SOX17) markers 3 . The gene expression profile of ECs is highly similar to embryonic stem cells (ESCs), hallmarked by expression of pluripotency markers (LIN28, NANOG, POU5F1 (OCT4), TFAP2C, GDF3, DNMT3B, TDGF1, SOX2) 3 .…”

Section: Introductionmentioning

confidence: 99%

“…they express pluripotency (LIN28, NANOG, POU5F1 (OCT4)) and PGC (PRDM1, TFAP2C, DMRT1, cKIT, SOX17) markers 3 . The gene expression profile of ECs is highly similar to embryonic stem cells (ESCs), hallmarked by expression of pluripotency markers (LIN28, NANOG, POU5F1 (OCT4), TFAP2C, GDF3, DNMT3B, TDGF1, SOX2) 3 . Interestingly, seminomas are SOX17+ and SOX2-, while ECs are SOX17-and SOX2+ 4 .…”

Section: Introductionmentioning

confidence: 99%

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Unique and redundant roles of SOX2 and SOX17 in regulating the germ cell tumour fate

Jostes

Fellermeyer

Merges

et al. 2019

Preprint

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Embryonal carcinomas (ECs) and seminomas are testicular germ cell tumours. ECs display expression of SOX2, while seminomas display expression of SOX17. In somatic differentiation, SOX17 drives endodermal cell fate. However, seminomas lack expression of endoderm markers, but show features of pluripotency. Here, we use ChIP-sequencing to report and compare the binding pattern of SOX17 in seminoma-like TCam-2 cells to SOX2 in EC-like 2102EP cells and SOX17 in somatic cells. In seminoma-like cells, SOX17 was detected at canonical (SOX2/OCT4), compressed (SOX17/OCT4) and other SOX family member motifs. SOX17 directly regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and supressing somatic differentiation. In contrast, in somatic cells canonical motifs are not bound by SOX17. In sum only 10% of SOX17 binding sites overlap in seminoma-like and somatic cells. This illustrates that binding site choice is highly dynamic and cell type specific. Deletion of SOX17 in seminoma-like cells resulted in loss of pluripotency, marked by a reduction of OCT4 protein level and loss of alkaline phosphatase activity. Further, we found that in EClike cells SOX2 regulates pluripotency-associated genes, predominantly by partnering with OCT4. In conclusion, SOX17 (in seminomas) functionally replaces SOX2 (in ECs) to maintain expression of the pluripotency cluster.

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Elucidating human male germ cell development by studying germ cell cancer

Cited by 13 publications

References 138 publications

Meta-Analysis of Gene Expressions in Testicular Germ Cell Tumor Histologies

Meta-Analysis of Gene Expressions in Testicular Germ Cell Tumor Histologies

Links between DNA Replication, Stem Cells and Cancer

Unique and redundant roles of SOX2 and SOX17 in regulating the germ cell tumour fate

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