Genomic and Expression Profiling of Human Spermatocytic Seminomas: Primary Spermatocyte as Tumorigenic Precursor and<i>DMRT1</i>as Candidate Chromosome 9 Gene

Looijenga, Leendert H. J.; Hersmus, Remko; Gillis, Ad J. M.; Pfundt, Rolph; Stoop, Hans; Gurp, Ruud J.H.L.M. van; Veltman, Joris A.; Beverloo, H. Berna; Drunen, Ellen van; Kessel, Ad Geurts van; Pera, Renee Reijo; Schneider, Dominik T.; Summersgill, Brenda; Shipley, Janet; McIntyre, Alan; Spek, Peter van der; Schoenmakers, Eric; Oosterhuis, J. Wolter

doi:10.1158/0008-5472.can-05-2936

Cited by 212 publications

(190 citation statements)

References 56 publications

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“…It is interesting to note that spermatocytic seminomas, which are TGCTs with a separate pathogenesis from seminoma, show strong expression of seladin-1. Our finding is in line with previous reports showing important differences between the set of genes overexpressed in seminoma compared with spermatocytic seminoma [37,38]. Genes that are overexpressed in spermatocytic seminoma are mainly related to spermatogenesis (especially those involved in the induction of meiosis), whereas seminoma shows up-regulation of genes involved in stem cell renewal.…”

Section: Discussionsupporting

confidence: 93%

Seladin‐1 and testicular germ cell tumours: new insights into cisplatin responsiveness

Nuti

Luciani

Marinari

et al. 2009

The Journal of Pathology

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The molecular basis for the exquisite sensitivity of testicular germ cell tumours of adolescents and adults (TGCTs), ie seminomas and non-seminomatous germ cell tumours, to chemo/radiotherapy has not been fully clarified so far. It has been suggested that it may be dependent on factors involved in the regulation of apoptosis. Seladin-1 is a multi-functional protein involved in various biological processes, including apoptosis. The aim of our study was to assess the expression of seladin-1 in different histological types of TGCTs, known to have varying treatment sensitivity, in order to establish whether this protein may influence cisplatin responsiveness in vitro. Seladin-1 expression levels, both at the mRNA and at the protein level, were higher in the adjacent normal parenchyma than in the pathological counterparts. In tumoural tissues, the level of expression differed among TGCT histological types. The highest tumour-expression level was found in teratoma, whereas the lowest was detected in seminoma, corresponding to the different chemo/and radiosensitivities of these tumour types. In common with other cancers, in TGCT-derived cell lines seladin-1 showed anti-apoptotic properties through inhibition of caspase-3 activation. We confirmed our results using a non-seminomatous cell line model (NT2) before and after differentiation with retinoic acid. Significantly higher seladin-1 expression was observed in the differentiated derivatives (teratoma) and an inverse relationship was found between seladin-1 expression and the amount of cleaved caspase-3. Seladin-1 silencing or overexpression in this cell line supports involvement of seladin-1 in cisplatin responsiveness. Seladin-1 silencing was associated with greater cisplatin responsiveness demonstrated by decreased cell viability and increased expression of apoptotic markers. In contrast, overexpression of seladin-1 was associated with a higher survival rate and a clear anti-apoptotic effect. In conclusion, we have demonstrated for the first time an important role for seladin-1 in the biology of TGCTs and provided new insights into cisplatin responsiveness of these tumours.

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Section: Discussionsupporting

confidence: 93%

Seladin‐1 and testicular germ cell tumours: new insights into cisplatin responsiveness

Nuti

Luciani

Marinari

et al. 2009

The Journal of Pathology

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“…Therefore, our data support the common hypothesis of a different cell origin concerning spermatocytic seminoma and classic seminoma. 1,35 Although intratubular germ cell neoplasia unclassified is considered to be derived from developmentally arrested gonocytes, 2,[36][37][38] there is some controversy about the progenitor 39 Previous studies suspected primary spermatocytes 40 or spermatogonia 35,41 as progenitor cells. In our study, we found a strong expression of cancer testis antigens in spermatogonia and in spermatocytic seminoma, which is consistent with an origin of spermatocytic seminoma from spermatogonia, too.…”

Section: Discussionmentioning

confidence: 99%

Cancer testis antigen expression in testicular germ cell tumorigenesis

et al. 2014

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Cancer testis antigens are encoded by germ line-associated genes that are present in normal germ cells of testis and ovary but not in differentiated tissues. Their expression in various human cancer types has been interpreted as 're-expression' or as intratumoral progenitor cell signature. Cancer testis antigen expression patterns have not yet been studied in germ cell tumorigenesis with specific emphasis on intratubular germ cell neoplasia unclassified as a precursor lesion for testicular germ cell tumors. Immunohistochemistry was used to study MAGEA3, MAGEA4, MAGEC1, GAGE1 and CTAG1B expression in 325 primary testicular germ cell tumors, including 94 mixed germ cell tumors. Seminomatous and non-seminomatous components were separately arranged and evaluated on tissue microarrays. Spermatogonia in the normal testis were positive, whereas intratubular germ cell neoplasia unclassified was negative for all five CT antigens. Cancer testis antigen expression was only found in 3% (CTAG1B), 10% (GAGE1, MAGEA4), 33% (MAGEA3) and 40% (MAGEC1) of classic seminoma but not in nonseminomatous testicular germ cell tumors. In contrast, all spermatocytic seminomas were positive for cancer testis antigens. These data are consistent with a different cell origin in spermatocytic seminoma compared with classic seminoma and support a progression model with loss of cancer testis antigens in early tumorigenesis of testicular germ cell tumors and later re-expression in a subset of seminomas.

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“…These regions included known differences of 12p overexpression associated with TGCT (Rodriguez et al, 2003) and 9p21 associated with SSE (Looijenga et al, 2006). Novel differences included overexpression from 4q22 and 5q23.2 associated with SSE.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike the TGCT of adults and adolescents, gain of 12p material is not a feature of these tumours. However, gain of chromosome 9 is associated with SSE and array comparative genomic hybridisation analysis identified amplification of 9p21.3-ter and the likely involvement of the DMRT1 gene (Looijenga et al, 2006). Cytogenetic, comparative genomic hybridisation (CGH) and allelic imbalance studies of SE and NS have shown that a number of regions in addition to 12p are imbalanced.…”

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confidence: 99%

Genomic copy number and expression patterns in testicular germ cell tumours

McIntyre

Summersgill

et al. 2007

Br J Cancer

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Testicular germ cell tumours of adults and adolescents (TGCT) include seminomas (SE) and nonseminomas (NS), with spermatocytic seminomas (SSE) representing a distinct entity in older men. SE and NS have gain of 12p material in all cases, whereas SSE are associated with overrepresentation of chromosome 9. Here, we compare at the chromosomal level, copy number imbalances with global expression changes, identified by comparative expressed sequence hybridisation analyses, in seven SE, one combined tumour, seven NS and seven cell lines. Positive correlations were found consistent with copy number as a main driver of expression change, despite reported differences in methylation status in SE and NS. Analysis of chromosomal copy number and expression data could not distinguish between SE and NS, in-keeping with a similar genetic pathogenesis. However, increased expression from 4q22, 5q23.2 and 9p21 distinguished SSE from SE and NS and decreased copy number and expression from 2q36 -q37 and 6q24 was a specific feature of NS-derived cell lines. Our analysis also highlights 19 regions with both copy number and expression imbalances in greater than 40% of cases. Mining available expression array data identified genes from these regions as candidates for involvement in TGCT development. Supplementary data is available at

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Genomic and Expression Profiling of Human Spermatocytic Seminomas: Primary Spermatocyte as Tumorigenic Precursor andDMRT1as Candidate Chromosome 9 Gene

Cited by 212 publications

References 56 publications

Seladin‐1 and testicular germ cell tumours: new insights into cisplatin responsiveness

Seladin‐1 and testicular germ cell tumours: new insights into cisplatin responsiveness

Cancer testis antigen expression in testicular germ cell tumorigenesis

Genomic copy number and expression patterns in testicular germ cell tumours

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