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Testicular Germ Cell Tumors (testicular + germ_cell_tumor)

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Medical Sciences	95%

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Genes, chromosomes and the development of testicular germ cell tumors of adolescents and adults

GENES, CHROMOSOMES AND CANCER, Issue 7 2008
Alan McIntyre
Testicular germ cell tumors (TGCTs) of adults and adolescents are thought to be derived from primordial germ cells or gonocytes. TGCTs develop postpuberty from precursor lesions known as intratubular germ cell neoplasia undifferentiated. The tumors can be divided into two groups based on their histology and clinical behavior; seminomas resemble primordial germ cells or gonocytes and nonseminomas resemble embryonic or extraembryonic tissues at various stages of differentiation. The most undifferentiated form of nonseminoma, embryonal carcinoma, resembles embryonic stem cells in terms of morphology and expression profiling, both mRNAs and microRNAs. Evidence supports both environmental factors and genetic predisposition underlying the development of TGCTs. Various models of development have been proposed and are discussed. In TGCTs, gain of material from the short arm of chromosome 12 is invariable: genes from this region include the proto-oncogene KRAS, which has activating mutations in ,10% of tumors or is frequently overexpressed. A number of different approaches to increase the understanding of the development and progression of TGCTs have highlighted the involvement of KIT, RAS/RAF/MAPK, STAT, and PI3K/AKT signaling. We review the role of these signaling pathways in this process and the potential influence of environmental factors in the development of TGCTs. © 2008 Wiley-Liss, Inc. [source]

Further characterization of the first seminoma cell line TCam-2

GENES, CHROMOSOMES AND CANCER, Issue 3 2008
Jeroen de Jong
Testicular germ cell tumors of adolescents and adults (TGCTs) can be classified into seminomatous and nonseminomatous tumors. Various nonseminomatous cell lines, predominantly embryonal carcinoma, have been established and proven to be valuable for pathobiological and clinical studies. So far, no cell lines have been derived from seminoma which constitutes more than 50% of invasive TGCTs. Such a cell line is essential for experimental investigation of biological characteristics of the cell of origin of TGCTs, i.e., carcinoma in situ of the testis, which shows characteristics of a seminoma cell. Before a cell line can be used as model, it must be verified regarding its origin and characteristics. Therefore, a multidisciplinary approach was undertaken on TCam-2 cells, supposedly the first seminoma cell line. Fluorescence in situ hybridization, array comparative genomic hybridization, and spectral karyotyping demonstrated an aneuploid DNA content, with gain of 12p, characteristic for TGCTs. Genome wide mRNA and microRNA expression profiling supported the seminoma origin, in line with the biallelic expression of imprinted genes IGF2/H19 and associated demethylation of the imprinting control region. Moreover, the presence of specific markers, demonstrated by immunohistochemistry, including (wild type) KIT, stem cell factor, placental alkaline phosphatase, OCT3/4 (also demonstrated by a specific Q-PCR) and NANOG, and the absence of CD30, SSX2-4, and SOX2, confirms that TCam-2 is a seminoma cell line. Although mutations in oncogenes and tumor suppressor genes are rather rare in TGCTs, TCam-2 had a mutated BRAF gene (V600E), which likely explains the fact that these cells could be propagated in vitro. In conclusion, TCam-2 is the first well-characterized seminoma-derived cell line, with an exceptional mutation, rarely found in TGCTs. © 2007 Wiley-Liss, Inc. [source]

Endogenous DNA damage and testicular germ cell tumors

INTERNATIONAL JOURNAL OF ANDROLOGY, Issue 6 2009
M. B. Cook
Summary Testicular germ cell tumors are comprised of two histologic groups, seminomas and non-seminomas. We postulated that the possible divergent pathogeneses of these histologies may be partially explained by variable levels of net endogenous DNA damage. To test our hypothesis, we conducted a case,case analysis of 51 seminoma and 61 non-seminoma patients using data and specimens from the Familial Testicular Cancer study and the U.S. Radiologic Technologists cohort. A lymphoblastoid cell line was cultured for each patient and the alkaline comet assay was used to determine four parameters: tail DNA, tail length, comet distributed moment (CDM) and Olive tail moment (OTM). Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. Values for tail length, tail DNA, CDM and OTM were modelled as categorical variables using the 50th and 75th percentiles of the seminoma group. Tail DNA was significantly associated with non-seminoma compared with seminoma (OR50th percentile = 3.31, 95% CI: 1.00, 10.98; OR75th percentile = 3.71, 95% CI: 1.04, 13.20; p for trend = 0.039). OTM exhibited similar, albeit statistically non-significant, risk estimates (OR50th percentile = 2.27, 95% CI: 0.75, 6.87; OR75th percentile = 2.40, 95% CI: 0.75, 7.71; p for trend = 0.12) whereas tail length and CDM showed no association. In conclusion, the results for tail DNA and OTM indicate that net endogenous levels are higher in patients who develop non-seminoma compared with seminoma. This may partly explain the more aggressive biology and younger age-of-onset of this histologic subgroup compared with the relatively less aggressive, later-onset seminoma. [source]

Brain metastases from testicular germ cell tumors: A retrospective analysis

INTERNATIONAL JOURNAL OF UROLOGY, Issue 11 2009
Norio Nonomura
Objectives: To review our series of testicular germ cell tumors with brain metastases and to establish an optimal treatment strategy for them. Methods: Twenty-seven cases of testicular germ cell tumors from three institutions were retrospectively reviewed. Results: Twenty-six were non-seminomatous tumors and only one was a seminoma. Based on the International Germ Cell Consensus Classification, two cases were classified as good prognosis, seven as intermediate prognosis and 18 as poor prognosis. Chemotherapy was carried out in all patients. Additionally, whole-brain radiotherapy was performed in 10 cases, stereotactic radiosurgery in six, whole-brain radiotherapy combined with stereotactic radiosurgery in three and complete surgical resection in five. Three patients received chemotherapy only. Cancer-specific 5- and 10-year survival rates were both 35.9%. The prognosis of those with brain metastases at the time of diagnosis tended to be better than those developing brain metastases during treatment. Those with a single brain metastasis showed significantly better survival than those with multiple brain metastases. No other significant prognostic factor was found at multivariate analysis. Conclusion: Testicular germ cell tumors with brain metastases can be managed with the combination of whole-brain radiotherapy, stereotactic radiotherapy, and/or surgical resection in combination with chemotherapy. [source]

Testis sparing surgery for the treatment of a sequential bilateral testicular germ cell tumor

INTERNATIONAL JOURNAL OF UROLOGY, Issue 12 2001
ZIYA KIRKALI
Abstract Standard therapy of sequential bilateral testis cancer is generally considered to be orchiectomy. We present a case of sequential bilateral testicular germ cell tumor treated with testis sparing surgery. The patient was disease free 50 months after surgery without local recurrence or distant metastases. Testis sparing surgery provides a better quality of life and may be considered a safe, feasible alternative in the treatment of carefully selected patients with bilateral testicular germ cell tumor. [source]

Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma

CANCER, Issue 10 2005
Uche I. Ezeh M.D.
Abstract BACKGROUND The seminoma class of testicular germ cell tumor (TGCT) are characterized by a morphological resemblance to primordial germ cells (PGCs) or gonocytes, and chromosome duplications at 12p. Recently, it was determined that human embryonic stem cells (hESCs) express genes in common with PGCs, and that three of these genes, GDF3, STELLAR, and NANOG, are located on 12p. The current study was designed to identify whether expression of these 12p genes were elevated in seminoma relative to normal testis, and to determine whether elevated expression was unique to seminoma. METHODS Real-time polymerase chain reaction (PCR) and immunohistochemistry were used to assess gene expression in seminoma samples relative to normal testis and endpoint PCR was used to identify the presence or absence of these genes in breast carcinoma. RESULTS GDF3 expression was increased in eight of nine seminomas compared with normal testis, whereas NANOG, OCT4, or both were expressed at the highest levels in seminoma compared with all other markers analyzed. In addition, the NANOG protein was expressed in the majority of seminoma cells. The adult meiotic germ cell markers BOULE and TEKT1 were undetectable in seminoma, whereas the embryonic and adult germ cell markers DAZL and VASA were significantly reduced. Analysis of these markers in breast carcinoma and the MCF7 breast carcinoma cell line revealed that a core hESC-transcriptional profile could be identified consisting of OCT4, NANOG, STELLAR, and GDF3 and that NANOG protein could be detected in breast carcinoma. CONCLUSIONS These observations suggest that seminoma and breast carcinoma express a common stem cell profile and that the expression of DAZL and VASA in seminoma mark the germ cell origin of seminoma that is absent in breast carcinoma. Our findings suggest that stem cell genes may either play a direct role in different types of carcinoma progression or serve as valuable markers of tumorigenesis. Cancer 2005. © 2005 American Cancer Society. [source]

Testicular carcinoma and HLA Class II genes

CANCER, Issue 9 2002
Dirk J. A. Sonneveld M.D., Ph.D.
Abstract BACKGROUND The association with histocompatibility antigens (HLA), in particular Class II genes (DQB1, DRB1), has recently been suggested to be one of the genetic factors involved in testicular germ cell tumor (TGCT) development. The current study, which uses genotyping of microsatellite markers, was designed to replicate previous associations. METHODS In 151 patients, along with controls comprising parents or spouses, the HLA region (particularly Class II) on chromosome 6p21 was genotyped for a set of 15 closely linked microsatellite markers. RESULTS In both patients and controls, strong linkage disequilibrium was observed in the genotyped region, indicating that similar haplotypes are likely to be identical by descent. However, association analysis and the transmission disequilibrium test did not show significant results. Haplotype sharing statistics, a haplotype method that derives extra information from phase and single marker tests, did not show differences in haplotype sharing between patients and controls. CONCLUSION The current genotyping study did not confirm the previously reported association between HLA Class II genes and TGCT. As the HLA alleles for which associations were reported are also prevalent in the Dutch populations, these associations are likely to be nonexistent or much weaker than previously reported. Cancer 2002;95:1857,63. © 2002 American Cancer Society. DOI 10.1002/cncr.10903 [source]

Genes, chromosomes and the development of testicular germ cell tumors of adolescents and adults

Genome profiles of familial/bilateral and sporadic testicular germ cell tumors

GENES, CHROMOSOMES AND CANCER, Issue 2 2002
Sigrid Marie Kraggerud
In order to investigate the genetics of testicular germ cell tumors (TGCTs), we examined 33 TGCTs, including 15 familial/bilateral and 18 sporadic tumors, using comparative genomic hybridization. The frequencies of the histological subtypes were comparable between the two groups. Gains of the whole or parts of chromosome 12 were found in 30 tumors (91%). Furthermore, increased copy number of the whole or parts of chromosomes 7, 8, 17, and X, and decreased copy number of the whole or parts of chromosomes 4, 11, 13, and 18 were observed in ,50% of the tumors. Sixteen smallest regions of overlapping changes were delineated on 12 different chromosomes. The chromosomal copy numbers of familial/bilateral and sporadic TGCTs were comparable, suggesting similar genetic pathways to disease in both groups. However, significant differences were observed between the two main histological subgroups. Gains from 15q and 22q were associated with seminomas (P = 0.005 and P = 0.02, respectively), whereas gain of the proximal 17q (17q11.2,21) and high-level amplification from chromosome arm 12p, and losses from 10q were associated with nonseminomas (P < 0.001, P = 0.04, and P = 0.03, respectively). © 2002 Wiley-Liss, Inc. [source]

Endogenous DNA damage and testicular germ cell tumors

Brain metastases from testicular germ cell tumors: A retrospective analysis

Paclitaxel, ifosfamide, and nedaplatin (TIN) salvage chemotherapy for patients with advanced germ cell tumors

INTERNATIONAL JOURNAL OF UROLOGY, Issue 6 2007
Norio Nonomura
Background: The paclitaxel, ifosfamide, and cisplatin regimen has been used to treat metastatic testicular cancer with successful results. We investigated the usefulness of a paclitaxel, ifosfamide, and nedaplatin (TIN) regimen as salvage therapy for patients with advanced testicular germ cell tumors (GCTs). Methods: Eight patients with advanced GCTs were treated with TIN. The treatment was performed as salvage therapy for cases refractory to therapies, such as bleomycin, etoposide and cisplatin, and irinotecan with nedaplatin. The TIN regimen consisted of paclitaxel (200 mg/m2) by 24-h infusion on day 1, followed by ifosfamide (1.2 g/m2) infusions over 2 h on days 2,6, and nedaplatin (100 mg/m2) given over 2 h on day 2. Results: Seven out of eight patients achieved a disease-free status after chemotherapy, followed by surgical resection of the residual tumor. Six of the seven patients have continued to show no evidence of disease after salvage therapy, with a median follow-up period of 27 months, but one patient developed a ,growing teratoma syndrome' in the mediastinum 31 months after TIN chemotherapy. All patients developed grade 4 leukocytopenia. However, it could be managed by using granulocyte colony-stimulating factor. Only one patient developed grade 2 sensory neuropathy and no patient developed nephrotoxicity. Conclusion: The TIN regimen was efficacious and well-tolerated as salvage chemotherapy for Japanese patients with advanced GCTs. [source]

Incorporation of TIP (paclitaxel, ifosfamide, cisplatin) into first-line therapy for intermediate to poor risk testicular germ cell tumors with unfavorable marker decline after initial two cycles chemotherapy: A report of three cases

INTERNATIONAL JOURNAL OF UROLOGY, Issue 5 2007
Jun-Ichiro Ishioka
Abstract: Three patients of advanced-non-seminomatous germ cell tumors (International Germ Cell Cancer Collaborative Group classification: poor risk, 2; intermediate, 1) without evidence of a second primary germ cell tumor were treated. The patients received two cycles of standard BEP (bleomycin, etopside, cisplatin) or VIP/VB (etoposide, ifosphamide, cisplatin/vinblastine, bleomycin) therapy first. All patients in this trial showed unfavorable marker response to these therapies and received four cycles of TIP subsequently. A complete remission was observed in all patients. No patient experienced life-threatening toxicity. During the 34-month observation period, all patients were alive without progression. [source]

Lack of association between the incidence of testicular germ cell tumors and Y-chromosome haplogroups in the Japanese population

INTERNATIONAL JOURNAL OF UROLOGY, Issue 9 2006
ASHRAF A EWIS
Background: Despite being relatively uncommon, testicular germ cell tumors (TGCT) are the most common malignant disease in young men. Epidemiological studies concerning patients with testicular cancer indicate that the most of them have poor semen quality or testicular dysgenesis. However, many studies have shown that the Y chromosome harbors many candidate genes responsible for spermatogenesis process and development and maintenance of the germ cells. The Y chromosome is thought to have a relationship with the formation and progression of TGCT. Materials and methods: To verify this relationship, we investigated if there is any correlation between the Y chromosome structural variations presented as different haplogroups and the occurrence of TGCT in the Japanese population. Using combined haplogroups based on typing of three Y chromosome polymorphic binary markers, we analyzed 68 TGCT derived from Japanese patients together with randomly selected 104 unrelated healthy Japanese matched male controls who were confirmed as residents of the same geographic area. Results: Our findings showed a lack of association between the incidence of TGCT and the different Y- chromosome haplogroups in Japanese population. Conclusion: We concluded that there are no significant variations in males from different Y chromosome lineages regarding their susceptibility or resistance for developing TGCT. The previously hypothesized role of the Y chromosome in the development of TGCT is still uncertain and needs further verification. [source]

Bis(4,7-dimethyl and 5-dinitro-1,10-phenanthroline) sulfato-oxovanadium(IV)-mediated in vivo male germ cell apoptosis

JOURNAL OF APPLIED TOXICOLOGY, Issue 4 2001
Osmond J. D'Cruz
Abstract Oxovanadium(IV) [VO] complexes of 1,10-phenanthroline are a new class of potent apoptosis-inducing cytotoxic agents against human testicular cancer cells in vitro. The present study investigated the in vivo ability of four(bis)-chelated 1,10-phenanthroline [phen] complexes of sulfato-oxovanadium(IV),VO(phen)2, VO(Cl,phen)2, VO(Me2,phen)2 and VO(NO2,phen)2,with and without substitutions, to induce testicular germ cell apoptosis. Male germ cell loss in mice was measured by determining the epididymal sperm count, testicular weight and histological evaluation of the testes. Repetitive intratesticular injection (7.5 mg kg,1 testis,1) of bis-chelated 1,10-phenanthroline complexes of oxovanadium(IV) with 4,7-dimethyl [VO(Me2,phen)2] and 5-dinitro [VO(NO2,phen)2] substitution led to decreased sperm counts and reduced testicular weights. Histopathological examination of testicular sections from VO(Me2,phen)2 - and VO(NO2,phen)2 -treated mice revealed a marked inhibition of spermatogenesis and preferential loss of maturing, as well as elongated spermatids. In situ evaluation of seminiferous tubule cross-sections by terminal deoxynucleotidyl transferase-mediated FITC-deoxyuridine triphosphate nick end-labeling (TUNEL) and laser scanning confocal microscopy showed characteristic apoptotic germ cells delineating the periphery of the seminiferous tubules. The ability of bis-chelated 4,7-dimethyl- and 5-dinitro-substituted 1,10-phenanthroline complexes of oxovanadium(IV) to induce germ cell apoptosis in vivo may have potential utility in the treatment of human testicular germ cell tumors. Copyright © 2001 John Wiley & Sons, Ltd. [source]

Elevation of XPA protein level in testis tumor cells without increasing resistance to cisplatin or UV radiation

MOLECULAR CARCINOGENESIS, Issue 8 2008
Beate Köberle
Abstract Most testicular germ cell tumors are curable using cisplatin-based chemotherapy, and cell lines from these tumors are unusually sensitive to cisplatin and other DNA-damaging agents. It has been suggested that this might be caused by a lower-than normal nucleotide excision repair (NER) activity. Previous studies found that cell lines from testicular germ cell tumors have on average about one-third the level of the NER protein XPA in comparison to cell lines from other tumors. We asked whether over-expression of XPA protein would alleviate the cellular sensitivity and increase the DNA repair capacity of a testis tumor cell line. Increasing XPA levels in 833K cells by 10-fold did not increase resistance to UV irradiation. XPA was localized to the cell nucleus in all cell lines, before and after exposure to UV-radiation. 833K cells were proficient in removing UV radiation-induced photoproducts from the genome and increased XPA did not enhance the rate of removal. Further, over-expressing functional XPA protein did not correlate with increased resistance of 833K testis tumor cells to cisplatin. Thus, although the amount of XPA in this testis tumor cell line is lower than normal, it is sufficient for NER in vivo. The relative sensitivity of testis tumor cells to cisplatin, UV radiation, and other DNA damaging agents is likely related not to NER capacity, but to other factors such as the integrity of the p53 pathway in these cells. © 2008 Wiley-Liss, Inc. [source]

Twist is inversely associated with claudins in germ cell tumors of the testis

APMIS, Issue 9 2010
PÄIVI VÄRE
Väre P, Soini Y. Twist is inversely associated with claudins in germ cell tumors of the testis. APMIS 2010; 118: 640,7. We investigated the expression of claudins 1, 3,7 and transcriptional factor twist in a set of testicular germ cell tumors. The material consisted of 17 seminomas, 13 teratomas, 9 teratocarcinomas, 20 embryonal carcinomas and 9 mixed germ cell tumors. They were immunostained with antibodies to claudins 1, 3,7 and twist. As expected, all claudins were variably present in germ cell tumors with epithelial elements or differentiation, but the intensity of expression varied depending on the claudin type. Mesenchymal elements in teratomatous tumors remained negative for claudins. Expression of different claudins was less intense and inconsistent in other types of germ cell tumors. Choriocarcinomatous elements in germ cell tumors expressed relatively strongly claudin 4 and weaker positivity for claudins 5,7, while claudins 1 and 3 were negative. Seminomas showed expression only for claudins 5 and 7. The transcriptional factor twist was most strongly expressed in seminoma followed by embryonal carcinoma. Twist expression was inversely associated with several claudins (claudins 1, 3, 4 and 6). Germ cell tumors vary in their expression of claudins 1,7. Twist expression was inversely associated with several claudins, suggesting that it takes part in the downregulation of claudins in testicular tumors. [source]

Alterations of the c-kit gene in testicular germ cell tumors

CANCER SCIENCE, Issue 6 2003
Yuji Sakuma
Expression and gain-of-function mutation of the c-kit gene, that encodes a receptor tyrosine kinase (KIT), have been reported in mast cell tumors and gastrointestinal stromal tumors (GISTs). Among human testicular germ cell tumors (GCTs), seminomas and seminoma components of mixed GCTs have also been shown to express KIT, but only one study has found the c-kit gene mutation at exon 17 in seminoma. To elucidate the frequency and location of the c-kit gene mutation of testicular GCTs, we analyzed the whole coding region of the c-kit complementary DNA along with 4 mutational hot spots (exons 9, 11, 13 and 17) of the c-kit genomic DNA by polymerase chain reaction and direct sequencing. Somatic mutations were found in 4 pure seminomas of 34 testicular GCTs (11.8%). One mutation was found in exon 11 (W557R) and the others were observed in exon 17 (D816H and D816V). These types of mutations were reported in GISTs (W557R), seminoma (D816H) and mastocytosis (D816V) and were considered to be gain-of-function mutations, although there were no differences of any clinicopathological factors or outcome between patients with and without mutations. Additionally, we also demonstrated coexpression of Gly-Asn-Asn-Lys510,513 (GNNK)+ and GNNK- isoforms of the c-kit gene with dominance of the GNNK- transcript in all testicular GCTs. The mutations and/or preferential expression of GNNK- isoform of the c-kit gene might play an important role in the development of testicular GCTs, and these tumors may also be targets for STI571, which is a promising drug for advanced and metastatic GISTs. [source]