CarcinomaIn situ of the testis: Review of biological and clinical features

Dieckmann, K.‐P.; Skakkebæk, Niels E.

doi:10.1002/(sici)1097-0215(19991210)83:6<815::aid-ijc21>3.0.co;2-z

Cited by 224 publications

(32 citation statements)

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“…First, the distinct and highly reproducible expression patterns of p19 INK4d in testicular tissues and tumours are consistent with the theory of origin of the human male germ-cell tumours from the primordial germ cells (Grigor and Wylie, 1998;Dieckmann and Skakkebñk, 1999;Skakkebñk et al, 1987). Second, our data shed new light on the puzzling issue of redundancy within the INK4 family of Cdk inhibitors (Ruas and Peters, 1998;Sherr and Roberts, 1999), in particular the question why p19 INK4d which shares its biochemical properties with the closely related p16 INK4a tumour suppressor, is apparently not targeted by mutations in cancer.…”

Section: Resultssupporting

confidence: 78%

“…This concept has prompted a new classi®cation of germ-cell tumours which is based on biological understanding of the histogenesis, and which proposes a term`gonocytoma' for seminomatous tumours and`gonocytoma in situ' for CIS (Grigor, 1993;Grigor and Wyllie, 1998). A major argument in favour of the above hypothesis comes from comparative analyses of foetal germ cells which share a number of morphological and biochemical features with CIS cells (Jùrgensen et al, 1995;Rajpert-De Meyts et al, 1998;Dieckmann and Skakkebñk, 1999). Given the evidence for high abundance of the p19 INK4d protein during human spermatogenesis (this study), and the structural and biochemical similarities of p19 INK4d with the p16 INK4a tumour suppressor (Ruas and Peters, 1998;Roussel, 1999), we wished to explore the potential role, if any, of p19 INK4d in human testicular germ-cell pathogenesis.…”

Section: Resultsmentioning

confidence: 99%

“…This trend, together with the worrying decline in male reproductive health, and the fascinating biology of the germ cells and germ-cell tumours (GCTs), have stimulated increased e orts to better understand the cellular and molecular biology of reproduction, and the molecular pathogenesis of testicular cancer (Andrews, 1998;Dieckmann and Skakkebñk, 1999;Grigor and Wylie, 1998;Skakkebñk et al, 1987). One of the unifying concepts emerging from these e orts is the notion that defects in the cell cycle machinery may signi®cantly contribute to oncogenesis in the human testis.…”

Section: Introductionmentioning

confidence: 99%

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Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

et al. 2000

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p19 INK4d , a member of the INK4 family of cyclindependent kinase inhibitors, negatively regulates the proto-oncogenic cyclin D/CDK4(6) complexes whose ability to phosphorylate the retinoblastoma tumour suppressor (RB) promotes G1/S transition. In contrast to the related p16 INK4a tumour suppressor, expression patterns of 19 INK4d in human tissues and tumours remain unknown. As the RB pathway is commonly targeted in cancer, and mouse models suggest a role for p19 INK4d in spermatogenesis, we examined the abundance and localization of p19 INK4d in the human testis, both during normal development and at various stages of germ-cell tumour pathogenesis. Our data show that the p19 INK4d protein is abundant in spermatocytes of normal human adult testes, whereas virtually no p19 INK4d is detectable in testicular cancer, including the preinvasive carcinoma in situ stage. Together with the lack of p19 INK4d in human foetal germ cells, these results support the concept of foetal origin of the testicular germ-cell tumours, and help better understand the emerging role of the RB pathway in spermatogenesis and tumorigenesis in the human testis. Oncogene (2000) 19, 4146 ± 4150.

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Section: Resultssupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

et al. 2000

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“…1,29 Smiraglia et al 14 have proposed a model whereby seminomas arise from IGCNU cells derived from primordial germ cells that have developed to the point whereby they have undergone 5 m C erasure. However, for nonseminomatous germ cell tumors, these authors proposed that they arise from IGCNU cells derived from primordial germ cells that had progressed past this point in their maturation in which they have undergone reprogramming by de novo methylation to contain normal 5 m C levels.…”

mentioning

confidence: 99%

Global DNA hypomethylation in intratubular germ cell neoplasia and seminoma, but not in nonseminomatous male germ cell tumors

et al. 2008

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Alterations in methylation of CpG dinucleotides at the 5 position of deoxycytidine residues (5mC) are a hallmark of cancer cells, including testicular germ cell tumors. Virtually all testicular germ cell tumors are believed to be derived from intratubular germ cell neoplasia unclassified (IGCNU), which is thought to arise from primordial germ cells. Prior studies revealed that seminomas contain reduced levels of global DNA methylation as compared with nonseminomatous germ cell tumors. Smiraglia et al have proposed a model whereby seminomas arise from IGCNU cells derived from primordial germ cells that have undergone 5mC erasure, and nonseminomas arise from IGCNU cells derived from primordial germ cells that have already undergone de novo methylation after the original erasure of methylation and contain normal 5mC levels. Yet the methylation status of IGCNU has not been determined previously. We used immunohistochemical staining against 5mC to evaluate global methylation in IGCNU and associated invasive testicular germ cell tumors. Strikingly, staining for 5mC was undetectable (or markedly reduced) in the majority of IGCNU and seminomas, yet there was robust staining in nonseminomatous germ cell tumors. The lack of staining for 5mC in IGCNU and seminomas was also found in mixed germ cell tumors containing both seminomatous and nonseminomatous components. Lack of 5mC staining was not related to a lack of the maintenance methyltransferase (DNA methyltransferase 1) protein. We conclude that testicular germ cell tumors are derived in most cases from IGCNU cells that have undergone developmentally programmed 5mC erasure and that the degree of subsequent de novo methylation is most closely related to the differentiation state of the neoplastic cells. That is, IGCNU cells and seminoma cells remain unmethylated, whereas all other histological types appear to arise after de novo methylation.

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“…Higher incidence of TGCTs in certain ethnic groups and in men with a family history of TGCTs [1-3] indicates a strong genetic predisposition to this cancer. Some of the genes, genetic loci and signaling pathways that contribute to TGCTs have been identified [4-9].…”

Section: Introductionmentioning

confidence: 99%

Tumor loci and their interactions on mouse chromosome 19 that contribute to testicular germ cell tumors

Zhu

Matin

2014

BMC Genet

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BackgroundComplex genetic factors underlie testicular germ cell tumor (TGCT) development. One experimental approach to dissect the genetics of TGCT predisposition is to use chromosome substitution strains, such as the 129.MOLF-Chr 19 (M19). M19 carries chromosome (Chr) 19 from the MOLF whereas all other chromosomes are from the 129 strain. 71% of M19 males develop TGCTs in contrast to 5% in 129 strain. To identify and map tumor loci from M19 we generated congenic strains harboring MOLF chromosome 19 segments on 129 strain background and monitored their TGCT incidence.ResultsWe found 3 congenic strains that each harbored tumor promoting loci that had high (14%-32%) whereas 2 other congenics had low (4%) TGCT incidences. To determine how multiple loci influence TGCT development, we created double and triple congenic strains. We found additive interactions were predominant when 2 loci were combined in double congenic strains. Surprisingly, we found an example where 2 loci, both which do not contribute significantly to TGCT, when combined in a double congenic strain resulted in greater than expected TGCT incidence (positive interaction). In an opposite example, when 2 loci with high TGCT incidences were combined, males of the double congenic showed lower than expected TGCT incidence (negative interaction). For the triple congenic strain, depending on the analysis, the overall TGCT incidence could be additive or could also be due to a positive interaction of one region with others. Additionally, we identified loci that promote bilateral tumors or testicular abnormalities.ConclusionsThe congenic strains each with their characteristic TGCT incidences, laterality of tumors and incidence of testicular abnormalities, are useful for identification of TGCT susceptibility modifier genes that map to Chr 19 and also for studies on the genetic and environmental causes of TGCT development. TGCTs are a consequence of aberrant germ cell and testis development. By defining predisposing loci and some of the locus interactions from M19, this study further advances our understanding of the complex genetics of TGCTs, which is the most common cancer in young human males.

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CarcinomaIn situ of the testis: Review of biological and clinical features

Cited by 224 publications

References 91 publications

Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

Global DNA hypomethylation in intratubular germ cell neoplasia and seminoma, but not in nonseminomatous male germ cell tumors

Tumor loci and their interactions on mouse chromosome 19 that contribute to testicular germ cell tumors

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