Gene Expression Profiling of Early- and Late-Relapse Nonseminomatous Germ Cell Tumor and Primitive Neuroectodermal Tumor of the Testis

Sugimura, Jun; Foster, Richard S.; Cummings, Oscar W.; Kort, Eric J.; Takahashi, Masayuki; Lavery, Todd T.; Furge, Kyle A.; Einhorn, Lawrence H.; Teh, Bin Tean

doi:10.1158/1078-0432.ccr-03-0341

Cited by 49 publications

(34 citation statements)

References 47 publications

(41 reference statements)

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“…Our fi nding on GATA-4 and GATA-6 expression is supported by recent gene expression profi ling in testicular GCTs that showed a 3.9-fold increase in the expression of these markers in YSTs as compared to other types of testicular GCTs [36] . We speculate that the expression of them, especially GATA-6, contributes to the formation of malignant yolk sac endoderm in GCTs.…”

Section: Discussionsupporting

confidence: 81%

Transcription Factors GATA-4 and GATA-6, and their Potential Downstream Effectors in Ovarian Germ Cell Tumors

Mannisto¹,

Bützow²,

Salonen³

et al. 2005

Tumor Biol

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Ovarian germ cell tumors (GCTs) are histologically heterogeneous neoplasms originating from activated germ cells, the oocyte stem cells. These rare tumors often contain many different tissues mixed together, and malignant components are occasionally hidden within benign tissues thus complicating the diagnosis. The reasons for the variable differentiation of germ cells are still largely unknown. As transcription factors GATA-4 and GATA-6 as well as their downstream factors (e.g. HNF-4, BMP-2 and Ihh) are essential for normal yolk sac development, we studied their expression in 19 ovarian GCTs. Endodermal markers were expressed distinctively in different GCT types. The malignant endoderm in yolk sac tumors expressed all factors of endodermal development included in the study. Dysgerminomas, on the contrary, expressed only GATA-4 and, in a minority of cases, Ihh and BMP-2. The results suggest that GATA-4 and GATA-6 detected in the ovarian GCTs have retained their normal function. The fact that GATA-6 and HNF-4 are expressed exclusively in endodermal tissues indicates that these transcription factors play a role in the differentiation of germ cells towards the endodermal phenotype. Analysis of the nuclear transcription factors in tumor tissue could serve as a new informative diagnostic tool for ovarian GCTs.

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Section: Discussionsupporting

confidence: 81%

Transcription Factors GATA-4 and GATA-6, and their Potential Downstream Effectors in Ovarian Germ Cell Tumors

Mannisto¹,

Bützow²,

Salonen³

et al. 2005

Tumor Biol

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“…CFLAR has an important role in regulation of apoptosis via the caspase pathway and therefore could be a therapeutic target (Yang, 2008), something that needs further evaluation. In addition, it has been shown that CFLAR can identify GCC patients with cisplatin resistance, based on genomewide expression analysis (Sugimura et al, 2004). Induction of c-FLIP has been reported in EC cell lines, as expected this results in resistance to cisplatin (Spierings et al, 2004).…”

Section: Cisplatin Sensitivity Of Germ Cell Cancersmentioning

confidence: 84%

Role of epigenetics in the etiology of germ cell cancer

Zwan¹,

Stoop²,

Rossello³

et al. 2013

Int. J. Dev. Biol.

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Embryonic development is strictly controlled by functionality of genes in which the existing networks can act both on transcription and translation regulation. Germ cell cancers (GCC) are unique because of a number of characteristics. In spite of their clinical presentation, i.e., predominantly after puberty, they arise from primordial germ cells/gonocytes that have failed appropriate maturation to either pre-spermatogonia or oogonia. GCC mimic embryonal development to a certain extent, including capacity for totipotency. This knowledge has allowed the identification of informative diagnostic markers, including OCT3/4 (POU5F1), SOX2 and SOX17. An additional marker is the overall demethylated status of the genome. Genetic mutations in GCC are rare, which is exceptional for solid cancers. Our hypothesis is that a disturbed epigenetic regulation (through combined interaction of genetic or environmental parameters; referred to as genvironment) affect embryonic germ cell development, resulting in delayed or blocked maturation, and potentially progression to GCC. In this respect, studies of patients with Disorders of Sex Development (DSD) have increased our knowledge significantly. Genvironmental influences can lead to retention of existence of embryonic germ cells, the first step in the pathogenesis of GCC, resulting into the precursor lesions gonadoblastoma or carcinoma in situ. Identification of epigenetic alterations could lead to better understanding these processes and development of specific markers for early detection, eventually leading to development of targeted treatment. This review describes an interactive model related to the role of epigenetics in GCC pathogenesis, focusing on DNA methylation, histone modifications, epigenetic memory and inheritance, as well as environmental factors.

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“…Gene expression profiling approaches have already been applied to the study of underlying transcriptomic alterations in GCTs. However, these studies were mainly performed on a limited number of samples, with only one GCT subtype dominating the whole data set (24,25). In contrast, our analysis was performed on a dataset with a balanced number of seminomas and nonseminomas, which enables more accurate determination of differentially expressed genes across these two groups.…”

Section: Gene Expression Signatures Of Histological Subtypes Of Gctmentioning

confidence: 99%

Gene expression profiling differentiates germ cell tumors from other cancers and defines subtype-specific signatures

Juric

Sale

Hromas

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Germ cell tumors (GCTs) of the testis are the predominant cancer among young men. We analyzed gene expression profiles of 50 GCTs of various subtypes, and we compared them with 443 other common malignant tumors of epithelial, mesenchymal, and lymphoid origins. Significant differences in gene expression were found among major histological subtypes of GCTs, and between them and other malignancies. We identified 511 genes, belonging to several critical functional groups such as cell cycle progression, cell proliferation, and apoptosis, to be significantly differentially expressed in GCTs compared with other tumor types. Sixty-five genes were sufficient for the construction of a GCT class predictor of high predictive accuracy (100% training set, 96% test set), which might be useful in the diagnosis of tumors of unknown primary origin. Previously described diagnostic and prognostic markers were found to be expressed by the appropriate GCT subtype (AFP, POU5F1, POV1, CCND2, and KIT). Several additional differentially expressed genes were identified in teratomas (EGR1 and MMP7), yolk sac tumors (PTPN13 and FN1), and seminomas (NR6A1, DPPA4, and IRX1). Dynamic computation of interaction networks and mapping to existing pathways knowledge databases revealed a potential role of EGR1 in p21-induced cell cycle arrest and intrinsic chemotherapy resistance of mature teratomas. testicular cancer ͉ unknown primary tumors ͉ DNA microarrays ͉ molecular interaction networks H uman germ cell tumors (GCTs) are a diverse group of neoplasms that most commonly arise in the gonads, particularly in the testis. They account for up to 60% of all malignancies diagnosed in men between 20 and 40 years of age. Their incidence (6-11 per 100,000) has increased among Caucasians in recent decades, with an annual increase of 3-6% (1).The histopathological classification of GCTs has been controversial because of the different concepts of histogenesis of these neoplasms, as well as the pluripotent nature of transformed primordial germ cells. GCTs can mimic normal patterns of embryonic segregation and differentiation, giving rise to structures resembling embryonic (endoderm, mesoderm, ectoderm) and extra-embryonic (yolk sac, trophoblast) derivatives. On the basis of the presence of those elements, they are further divided into pure GCTs (seminoma, embryonal carcinoma, teratoma, choriocarcinoma, and yolk sac tumor) or mixed GCTs, if more than one element is present.Compared with most cancers of adults, GCTs are highly sensitive to chemotherapy (2). Even with metastases, 80% of GCT patients can be cured by cisplatin-based combination chemotherapy, followed by secondary resection of residual tumor lesions, which can contain necrotic cells, viable malignant cells, or mature teratoma. In contrast to the other histological subtypes, mature teratomas show a less aggressive clinical behavior, but are unresponsive to chemotherapy. The biological bases for the chemosensitivity of GCTs and the clinical behavior of mature teratomas are unclear (3).In this study, ...

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Gene Expression Profiling of Early- and Late-Relapse Nonseminomatous Germ Cell Tumor and Primitive Neuroectodermal Tumor of the Testis

Cited by 49 publications

References 47 publications

Transcription Factors GATA-4 and GATA-6, and their Potential Downstream Effectors in Ovarian Germ Cell Tumors

Transcription Factors GATA-4 and GATA-6, and their Potential Downstream Effectors in Ovarian Germ Cell Tumors

Role of epigenetics in the etiology of germ cell cancer

Gene expression profiling differentiates germ cell tumors from other cancers and defines subtype-specific signatures

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