<i>N</i>‐ and <i>KRAS</i> mutations in primary testicular germ cell tumors: Incidence and possible biological implications

Olie, Robert A.; Looijenga, Leendert; Boerrigter, Lucie; Top, B.; Rodenhuis, S.; Langeveld, An; Mulder, Marlies; Oosterhuis, J. Wolter

doi:10.1002/gcc.2870120205

Cited by 53 publications

(31 citation statements)

References 17 publications

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“…Because we found one TGCT without expression of this gene, SOX5 does not seem to be the gene of interest. Involvement of KRAS2 in the pathogenesis of TGCTs has been suggested and questioned by di erent investigators and its role is largely unclear so far (Dmitrovsky et al, 1990;Moul et al, 1992;Olie et al, 1995). Moreover, it has been reported that activation of KRAS2 is not su cient for malignant transformation (Kumar et al, 1990;Rodenhuis, 1992;McCormick, 1994).…”

Section: Discussionmentioning

confidence: 99%

Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults

et al. 1998

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Cytogenetically, testicular germ cell tumors of adolescents and adults (TGCTs) are characterized by gain of 12p-sequences, most often through isochromosome formation (i(12p)). Fluorescence in situ hybridization (FISH) has shown that i(12p))-negative TGCTs also cryptically contain extra 12p-sequences. The consistency of 12p-over-representation in all histological subtypes of TGCTs, including their preinvasive stage, suggests that gain of one or more genes on 12p is crucial in the development of this cancer. So far, studies aimed at the identi®cation of the relevant gene(s) were based on thè candidate-gene approach'. No convincing evidence in favor of or against a particular gene has been reported. We combined conventional karyotyping, comparative genomic hybridization, and FISH to identify TGCTs with ampli®cations of restricted regions of 12p. Out of 49 primary TGCTs (23 without i(12p), 13 with and 13 unknown), eight tumors (six without i(12p) and two unknown) showed ampli®cations corresponding to 12p11.1-p12.1. Using bicolour-FISH, physical mapping, and semi-quantitative polymerase chain reactions, the size of the shortest region of overlap of ampli®cation (SROA) was estimated to be between 1750 ± 3000 kb. In addition, we mapped a number of genes in and around this region. While fourteen known genes could be excluded as candidates based on their location outside this region, we demonstrate that KRAS2, JAW1 and SOX5 genes are localized within the SROA. While KRAS2 and JAW1 map to the proximal border of the SROA, SOX5 maps centrally in the SROA. KRAS2 and JAW1 are expressed in all TGCTs, whereas one 12p amplicon-positive TGCT lacks expression of SOX5. The critical region of 12p over-represented in TGCTs is less than 8% of the total length of the short arm of chromosome 12. It will be helpful in the identi®cation of the gene(s) involved in TGCT-development.

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Section: Discussionmentioning

confidence: 99%

Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults

et al. 1998

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“…This supports a model in which overexpression of a gene or genes on 12p is related to the invasive growth of the tumor cells rather than initiation of tumorigenesis. Various attempts have been undertaken to identify the gene of interest, including KRAS2 (Mulder et al, 1989;Moul et al, 1992;Ridanpa¨a¨et al, 1993;Olie et al, 1995) and CCND2 (Sicinski et al, 1996;Houldsworth et al, 1997;Schmidt et al, 2001;Skotheim et al, 2002). However, formal proof that these genes are involved is missing so far.…”

Section: Introductionmentioning

confidence: 99%

12p-Amplicon structure analysis in testicular germ cell tumors of adolescents and adults by array CGH

et al. 2003

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All invasive testicular germ cell tumors of adolescents and adults (TGCTs), that is, seminomas and nonseminomas, show gain of 12p sequences, mostly as isochromosomes. Although several candidate genes have been suggested, the relevant gene(s) have not been identified yet. About 10% of testicular seminomas, however, show a more restricted amplification of the 12p11.2-p12.1 region, in which the various amplicons show an apparent overlap, allowing for the shortest region of amplification overlap approach, aiming at the identification of pathogenetically relevant sequences residing in this region. Here we report on a high-resolution 12p-amplicon architecture analysis using microarray-based comparative genomic hybridization, the results of which were subsequently confirmed by fluorescent in situ hybridization studies. The 12p-specific microarray contained 63 positionally selected BAC clones, which are more or less evenly distributed over the short arm of chromosome 12 (average spacing: less than 500 Kb), including 20 clones within the region of amplification. Out of a series of 17 seminomas, seven seminomas showed amplification of the whole amplicon region, of which three showed a dip in T/R value in the center of the amplified area. A more complex amplification pattern was found in the other 10 seminomas: three showed predominant amplification at the centromeric border; one mainly at the telomeric border; six showed a balanced amplification of both the centromeric and telomeric regions. The only nonseminoma investigated showed a structure in which the centromeric border was only amplified. These data support a mechanistic model in which at least two 12p genes, situated at the border regions of the amplicon, are positional candidates capable of actively supporting tumor progression in TGCTs.

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“…A small percentage of TGCTs has RAS mutations, [35][36][37] of which the clinical relevance was not studied. We showed previously that seminomas with a mutated RAS gene have survival advantage in vitro and have reduced apoptosis in the primary tumor.…”

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Restricted 12p Amplification and RAS Mutation in Human Germ Cell Tumors of the Adult Testis

Roelofs¹,

Mostert²,

Pompe

et al. 2000

The American Journal of Pathology

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Human testicular germ-cell tumors of young adults (TGCTs), both seminomas and nonseminomas, are characterized by 12p overrepresentation, mostly as isochromosomes, of which the biological and clinical significance is still unclear. A limited number of TGCTs has been identified with an additional highlevel amplification of a restricted region of 12p including the K-RAS proto-oncogene. Here we show that the incidence of these restricted 12p amplifications is ϳ8% in primary TGCTs. Within a single cell formation of i(12p) and restricted 12p amplification is mutually exclusive. The borders of the amplicons cluster in short regions, and the amplicon was never found in the adjacent carcinoma in situ cells. Seminomas with the restricted 12p amplification virtually lacked apoptosis and the tumor cells showed prolonged in vitro survival like seminoma cells with a mutated RAS gene. However, no differences in proliferation index between these different groups of seminomas were found. Although patients with a seminoma containing a homogeneous restricted 12p amplification presented at a significantly younger age than those lacking it, the presence of a restricted 12p amplification/RAS mutation did not predict the stage of the disease at clinical presentation and the treatment response of primary seminomas. In 55 primary and metastatic tumors from 44 different patients who failed cisplatinum-based chemotherapy, the restricted 12p amplification and RAS mutations had the same incidence as in the consecutive series of responding patients. These data support the model that gain of 12p in TGCTs is related to invasive growth. It allows tumor cells, in particular those showing characteristics of early germ cells (ie, the seminoma cells), to survive outside their specific microenvironment. Overexpression of certain genes on 12p probably inhibits apoptosis in these tumor cells. However, the copy numbers of the restricted amplification of 12p and K-RAS mutations do not predict response to therapy and survival of the patients. (Am J Pathol

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N‐ and KRAS mutations in primary testicular germ cell tumors: Incidence and possible biological implications

Cited by 53 publications

References 17 publications

Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults

Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults

12p-Amplicon structure analysis in testicular germ cell tumors of adolescents and adults by array CGH

Restricted 12p Amplification and RAS Mutation in Human Germ Cell Tumors of the Adult Testis

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