Distinct epigenetic phenotypes in seminomatous and nonseminomatous testicular germ cell tumors

Smiraglia, Dominic J.; Szymańska, Joanna; Kraggerud, Sigrid Marie; Lothe, Ragnhild; Peltomäki, Païvi; Plass, Christoph

doi:10.1038/sj.onc.1205488

Cited by 154 publications

(141 citation statements)

References 29 publications

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“…This may suggest that the total effect on expression levels of mechanisms other than chromosomal imbalances is similar in the different subtypes of TGCT. This is despite reported differences in the frequency of CpG island methylation of 0.08% in SE compared to 1.11% in NS (Smiraglia et al, 2002;Zhang et al, 2005).…”

Section: Discussionmentioning

confidence: 65%

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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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Section: Discussionmentioning

confidence: 65%

“…Factors predicted to influence gene expression include genomic copy number and epigenetic factors such as methylation. The level of methylation in TGCT varies between the subtypes and previous studies have found that SE have a lower level of CpG island methylation than NS (Smiraglia et al, 2002;Zhang et al, 2005).…”

mentioning

confidence: 94%

Genomic copy number and expression patterns in testicular germ cell tumours

McIntyre

Summersgill

et al. 2007

Br J Cancer

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“…This is in line with previously described differences in the epigenetic phenotype of SEMs and N-SEMs. The genome of N-SEMs appears to be more methylated than that of both CIS and SEMs (Smiraglia et al, 2002;Smith-Sorensen et al, 2002;Honorio et al, 2003). Teratomas are more differentiated than EC and the absence of DMNT3L expression in teratomas in the RT -PCR analysis could indicate that a demethylation of DNA occurs when an EC differentiates into a teratoma.…”

Section: Discussionmentioning

confidence: 98%

Genome-wide gene expression profiling of testicular carcinoma in situ progression into overt tumours

et al. 2005

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The carcinoma in situ (CIS) cell is the common precursor of nearly all testicular germ cell tumours (TGCT). In a previous study, we examined the gene expression profile of CIS cells and found many features common to embryonic stem cells indicating that initiation of neoplastic transformation into CIS occurs early during foetal life. Progression into an overt tumour, however, typically first happens after puberty, where CIS cells transform into either a seminoma (SEM) or a nonseminoma (N-SEM). Here, we have compared the genome-wide gene expression of CIS cells to that of testicular SEM and a sample containing a mixture of N-SEM components, and analyse the data together with the previously published data on CIS. Genes showing expression in the SEM or N-SEM were selected, in order to identify gene expression markers associated with the progression of CIS cells. The identified markers were verified by reverse transcriptase -polymerase chain reaction and in situ hybridisation in a range of different TGCT samples. Verification showed some interpatient variation, but combined analysis of a range of the identified markers may discriminate TGCT samples as SEMs or NSEMs. Of particular interest, we found that both DNMT3B (DNA (cytosine-5-)-methyltransferase 3 beta) and DNMT3L (DNA (cytosine-5-)-methyltransferase 3 like) were overexpressed in the N-SEMs, indicating the epigenetic differences between N-SEMs and classical SEM.

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“…In fact, DNA methylation seems to be a major mechanism for regulating gene expression in TGCT. [22][23][24] Finally, the expression of NKX3.1 seen in a subset of the most differentiated nonseminomas indicates that the loss of its expression in TGCT is reversible and thus likely caused by epigenetic silencing. The fact that none of the 70 embryonal carcinomas expressed NKX3.1 and the general view that the embryonal carcinomas are precursors for the differentiated nonseminomas support this assumption of reversibility.…”

Section: Discussionmentioning

confidence: 99%

NKX3.1 Expression Is Lost in Testicular Germ Cell Tumors

Skotheim

Korkmaz

Klokk

et al. 2003

The American Journal of Pathology

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NKX3.1 is a homeobox gene which exhibits prostate and testis specific expression. Loss of NKX3.1 expression has been implicated in prostate development and tumorigenesis, but the role of NKX3.1 in testis biology is not known. Here we show that NKX3.1 expression is dramatically down-regulated in testicular cancer of germ cell origin. Immunohistochemical analysis on a tissue microarray containing 510 testicular tissue samples indicate that NKX3.1 is expressed at high levels in normal germ cells and in carcinoma in situ, but is sharply decreased or absent in most seminomas and all embryonal carcinomas. However, NKX3.1 is expressed in a subset of the more differentiated nonseminomas. We provide evidence that these changes in NKX3.1 protein levels are mainly due to transcriptional effects. These results suggest that NKX3.1 is essential for normal testis function and that its loss of expression is highly associated with the invasive phenotype of testicular germ cell tumors. Testicular germ cell tumor (TGCT) is the most common malignancy among adolescents and young adult men in Western industrialized countries, and the incidence has increased dramatically over the past fifty years.

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Distinct epigenetic phenotypes in seminomatous and nonseminomatous testicular germ cell tumors

Cited by 154 publications

References 29 publications

Genomic copy number and expression patterns in testicular germ cell tumours

Genomic copy number and expression patterns in testicular germ cell tumours

Genome-wide gene expression profiling of testicular carcinoma in situ progression into overt tumours

NKX3.1 Expression Is Lost in Testicular Germ Cell Tumors

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