Seladin‐1 and testicular germ cell tumours: new insights into cisplatin responsiveness
Francesca NutiPaola LucianiEliana MarinariEdit ErdeiMihály BakCristiana DeleddaFabiana RosatiBenedetta MazzinghiGiovanna DanzaHans StoopLeendert H. J. LooijengaAlessandro PeriMario SerioCsilla Krausz
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Abstract 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. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.Embryonal carcinoma
Tumor progression
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419 Background: Patients with testicular germ cell tumor (TGCT) are at increased risk of developing a metachronous contralateral testicular tumor (CLTT). It is unclear whether the histology of the primary tumor and treatment with platinum-based chemotherapy are associated with the risk of CLTT. The primary aim of this study was to analyze the association between number of chemotherapy cycles and risk of CLTT. Methods: We evaluated the incidence of metachronous CLTT (≥2 months after diagnosis of primary TGCT) in a nationwide cohort consisting of patients diagnosed with TGCT between 1989 and 2007. Standardized incidence ratios (SIRs) were computed to compare CLTT incidence with TGCT in the general population and the cumulative incidence of CLTT was estimated. We analyzed the association between treatment with chemotherapy and risk of CLTT in a multivariate Cox-model. Results: The entire cohort consisted of 4,755 patients (seminoma: n=2,612; 54.9%, nonseminomatous germ cell tumor [NSGCT]: n=2,143; 45.1%). The median age at diagnosis was 33 years (IQR 26-40). A total of 1,047 patients (22.0%) were treated with platinum-based chemotherapy for their primary TGCT (seminoma: n=189, NSGCT: n=858). Median follow-up was 17.0 years (IQR 12.7-22.0). A CLTT was diagnosed in 136 patients. The median interval to CLTT diagnosis was 6.1 years (range 0.8-19.7). The overall 20-year cumulative incidence was 3.4% (95% CI 2.8-4.0) and was higher after seminoma (4.0%; 95% CI 3.3-4.9), compared to NSGCT (2.6%; 95% CI 1.9-3.4). The SIRs were for seminoma: 22.1 (95% CI 17.8-27.1), for NSGCT: 8.6 (95% CI 6.3-11.6) and for the entire cohort: 14.6 (95% CI 12.2-17.2). In multivariate analysis, the risk of developing a CLTT decreased with age (HR 0.93; 95% CI 0.90-0.96), was lower after NSGCT (HR 0.58; 95% CI 0.35-0.96), and decreased with every additional cycle of chemotherapy (HR 0.74; 0.64-0.85). This corresponds to a 26% lower risk of CLTT per extra chemotherapy cycle. Conclusions: TGCT patients have an almost 15 times higher risk of developing a CLTT, compared to the general population. The risk is 2 times higher after a seminoma, compared to NSGCT, and decreases with every additional cycle of chemotherapy. Especially in high risk patients, lifelong self-examination is advised.
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Incidental detection of urogenital tumors has increased in recent decades owing to the greater use of ultrasonography and cross-sectional imaging. For patients with low-risk prostate cancer or small renal masses, active surveillance represents a valid treatment option. Similarly, for men with small testicular masses <10 mm, active surveillance has been discussed as an alternative to surgery, although little is known regarding the behavior of small testicular germ cell tumors (GCTs). In the Swiss Austrian German Testicular Cancer Cohort Study we identified 849 patients (546 seminoma, 303 nonseminoma) treated with radical inguinal orchiectomy for GCT with a median tumor diameter of 35 mm. A tumor diameter <10 mm was observed in 25 patients (13 seminoma, 12 nonseminoma). Of these, five patients (20%) presented with primary metastatic disease, all of whom had elevated tumor markers and nonseminomatous GCTs. Two patients (8%) with initially localized disease (1 seminoma, 1 nonseminoma) and without elevated tumor markers experienced relapse at 4 mo (nonseminoma) and 14 mo (seminoma) after orchiectomy, despite the fact that the latter had received adjuvant chemotherapy. These findings highlight the metastatic potential of small testicular GCTs and raise the question of whether active surveillance for small testicular masses is safe.
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Comparative genomic hybridization
Interphase
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Objective: To investigate the expression of LRP,GST-πin the testicular germ cell tumor and evaluate their role in multidrug resistance of the testicular germ cell tumor.Methods: 41 samples of germ cell tumor without chemotherapy were analyzed immunohistochemically.Results: The total positive percentage of LRP in the testicular germ cell tumor was 41.5%,the frequence of LRP expression in Ⅰ stage,Ⅱ+Ⅲ stage,seminoma and non-seminoma germ cell tumor was 23.1%,73.3%,40.0% and 45.5% respectively.There was significant difference of the LRP expression between I stage and Ⅱ+Ⅲ stage in the testis germ cell tumor(P0.05).The total positive percentage of the expression of GST-π was 34.1%;the frequence of LRP expression in I stage,Ⅱ+Ⅲstage,seminoma and non-seminoma germ cell tumor was 38.5%,26.7%,30.0%and 45.5% respectively.The expression of GST-πwas not associated with clinical stage and pathological types(P0.05).Conclusion: The expression of LRP was correlational with the clinical stage of the testicular germ cell tumor,and LRP expression may be an important prediction of patients with testicular germ cell tumor.【
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A case of bilateral successive tumor of germ cell origin is reported. A 29-year-old man visited our clinic with a complaint of swelling of right scrotal contents 18 months after initial left orchiectomy for a seminoma. The right orchiectomy was performed and its histological finding was also seminoma. Between 1965-1987 we treated 55 patients with testicular germ cell tumors. Two of them suffered a second germ cell tumor. One of them who had different histology of teratocarcinoma on left side and seminoma on right side had been reported previously. Herein, we report the second case and review the literature.
Teratocarcinoma
Orchiectomy
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Embryonal carcinoma
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Human germ cell tumours comprise a heterogeneous group of neoplasms which, based on pathobiological, genetic and clinical characteristics, can be subdivided into different entities. One of these subgroups relates to the so-called spermatocytic seminomas, benign tumours only found in the testis, preferentially in elderly men. Various developmental models for this type of germ cell tumour have been proposed and it is clear that spermatocytic seminoma has a pathogenesis independent from that of seminoma. A recent study examining expression of spermatogonial markers shows that spermatocytic seminomas are a heterogeneous group of tumours, with a supposed difference in origin, ie the majority from A(pale) or B spermatogonia, and a minority from A(dark) spermatogonia. However, this does not exclude an earlier cell of origin, possibly explaining the unique properties of this type of human germ cell tumour, with various counterparts in animals.
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e15031 Background: Theetiology andreliable biomarkers for the risk of bilateral TGCT are still under investigation. Long-term relapse risks of up to 20 years after the therapy in contralateral testes demand a specific model of surveillance. Due to the rarity of the tumor type, reports of national experiences of bilateral TGCT are of a crucial significance for a future global database. Methods: The study was conducted during the treatment of 1 823 patients with TGCT in a single center from 1987-2011. Their mean age was 24 years at the time of diagnosis. Results: Out of 1 823 patients diagnosed with TGCT, 33 developed the bilateral disease (1.81%), 11 of them had synchronous tumors (33%). In the rest of patients the second testicular tumor was diagnosed 1 to 17 years after the initial diagnosis. The mean age of patients with bilateral TGCT was 28. According to the histological type: 11 were seminoma, 14 non-seminoma and 8 mixed seminoma and non-seminoma. Seven patients with bilateral tumor had a seminoma component at initial diagnosis. Compared to 5 patients out of 11 with synchronous tumor, the yolk sac component was detected only in 2 out of 22 metachronous patients. Conclusions: The presented findings of bilateral TGCT prevalence (1.8%) are in concordance with similar previous studies. As this type of tumor may be effectively treated, the risk assessment of metachronous tumor development should in future be facilitated by new biomarkers based on omics techniques. Thus, the investigation of karyotyping, c-KIT and transcriptome specificities will contribute to elucidation which pathways contribute to germ cell neoplasms. The stem cell markers for pluripotency maintenance may in future become potential diagnostic markers used as predictors for metastatic germ cell tumors. The development of a global database on these rare tumors will be of a crucial importance.
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Abstract Testicular germ cell tumour (TGCT) is a malignancy with known inherited risk factors, affecting young men. We have previously identified several hundred circulating RNAs that were differentially expressed in pre-diagnostic serum samples from TGCT cases when compared to healthy controls. In this study we performed network preservation analyses of pre-diagnostic serum mRNA and miRNA. Hub genes, enriched functional pathways, and regulatory feature prediction were identified for all TGCT, seminoma, and non-seminoma cases separately, compared to controls. We identified UBCA1, RCC1, FMR1, OSA3, and UBE2W as hub genes associated with TGCT. The genes OSA3 and UBE2W have previously been associated with testicular dysgenesis syndrome (TDS) disorders. Previously described TGCT susceptibility genes TEX14 , NARS2, and G3BP2 were identified as hub genes in both seminoma and non-seminoma networks. Furthermore, network module analysis showed prediction of transcription factors for oestrogen-related receptors. The overlap between network hub genes and TGCT susceptibility genes indicates a role in the progression from germ cell neoplasia in situ (GCNIS) to TGCT that should be further investigated.
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A 40-year-old, male, Japanese patient presented with the complaint of painless, right testicular swelling. Tumor markers for testicular cancer were normal. He underwent radical orchiectomy with the clinical diagnosis of stage I seminoma. Pathological examination revealed seminoma and coexisting neuroendocrine tumor (NET). Germ cell neoplasia in situ (GCNIS) was present in the vicinity of seminoma, but there was no continuity between NET and seminoma. Tumor cells of both lesions displayed amplification of 12p and isochromosome 12p on fluorescence in situ hybridization, suggesting that both tumors originated from GCNIS. The present report is the first to describe a case of primary testicular NET coexisting with seminoma in an ipsilateral testis.
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Isochromosome
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