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1.
Int J Cancer ; 146(6): 1592-1605, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31583686

RESUMO

Embryonal carcinomas (ECs) and seminomas are testicular germ cell tumors. ECs display expression of SOX2, while seminomas display expression of SOX17. In somatic differentiation, SOX17 drives endodermal cell fate. However, seminomas lack expression of endoderm markers, but show features of pluripotency. Here, we use chromatin immunoprecipitation sequencing to report and compare the binding pattern of SOX17 in seminoma-like TCam-2 cells to SOX17 in somatic cells and SOX2 in EC-like 2102EP cells. In seminoma-like cells, SOX17 was detected at canonical (SOX2/OCT4), compressed (SOX17/OCT4) and noncomposite SOX motifs. SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. In contrast, in somatic cells canonical motifs are rarely bound by SOX17. In sum, only 12% of SOX17-binding sites overlap in seminoma-like and somatic cells. This illustrates that binding site choice is highly dynamic and cell type specific. Deletion of SOX17 in seminoma-like cells resulted in loss of pluripotency, marked by a reduction of OCT4 protein level and loss of alkaline phosphatase activity. Furthermore, we found that in EC-like cells SOX2 regulates pluripotency-associated genes, most likely by partnering with OCT4. In conclusion, SOX17 (in seminomas) functionally replaces SOX2 (in ECs) to maintain expression of the pluripotency cluster.


Assuntos
Carcinoma Embrionário/genética , Neoplasias Embrionárias de Células Germinativas/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição SOXF/metabolismo , Seminoma/genética , Neoplasias Testiculares/genética , Animais , Carcinoma Embrionário/patologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Neoplasias Embrionárias de Células Germinativas/patologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Proteínas de Ligação a RNA/genética , Seminoma/patologia , Neoplasias Testiculares/patologia , Fator de Transcrição AP-2/genética , Fatores de Transcrição/genética , Ativação Transcricional/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Clinics (Sao Paulo) ; 74: e408, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31721911

RESUMO

This review describes the germ cell neoplasms that are malignant and most commonly associated with several types of gonadal dysgenesis. The most common neoplasm is gonadoblastoma, while others including dysgerminomas, yolk-sac tumors and teratomas are rare but can occur. The purpose of this review is to evaluate the incidences of these abnormalities and the circumstances surrounding these specific tumors.According to well-established methods, a PubMed systematic review was performed, to obtain relevant studies published in English and select those with the highest-quality data.Initially, the first search was performed using gonadal dysgenesis as the search term, resulting in 12,887 PubMed papers, published, from 1945 to 2017. A second search using ovarian germ cell tumors as the search term resulted in 10,473 papers, published from 1960 to 2017. Another search was performed in Medline, using germ cell neoplasia as the search term, and this search resulted in 7,560 papers that were published between 2003 to 2016, with 245 new papers assessing gonadoblastomas.The higher incidence of germ cell tumors in gonadal dysgenesis is associated with a chromosomal anomaly that leads to the absence of germ cells in these gonads and, consequently, a higher incidence of neoplasms when these tumors are located inside the abdomen. Several hypotheses suggest that increased incidence of germ cell tumors involves all or part of the Y chromosome or different genes.


Assuntos
Disgenesia Gonadal/genética , Neoplasias Embrionárias de Células Germinativas/classificação , Feminino , Humanos , Incidência , Masculino , Neoplasias Embrionárias de Células Germinativas/genética , Fatores de Risco
4.
Nat Genet ; 51(12): 1702-1713, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768071

RESUMO

Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Encéfalo/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Animais , Encéfalo/patologia , Linhagem Celular Tumoral , Humanos , Lactente , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Fibras Nervosas/patologia , Fibras Nervosas/fisiologia , Prosencéfalo/citologia , Prosencéfalo/embriologia , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Análise de Célula Única
5.
Curr Med Sci ; 39(5): 702-706, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612386

RESUMO

It has been reported that c-KIT ligand (KITLG) gene polymorphisms may be associated with testicular germ cell tumors (TGCT). Owing to mixed and inconclusive results, we conducted a systematic review and meta-analysis to summarize and clarify this association. A systematic search of studies on the association between KITLG gene polymorphisms and TGCT susceptibility was conducted in databases. Odds ratios and 95% confidence intervals were used to pool the effect size. Six articles were included in our systematic review and meta-analysis. Compared with adenine (A), KITLG rs995030 guanine (G) might be associated with increased risk of TGCT. There are insufficient data to fully confirm the association between KITLG rs4474514 and TGCT susceptibility. Well-designed studies with larger sample size and more subgroups are required to validate the risk identified in the current meta-analysis.


Assuntos
Predisposição Genética para Doença , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/genética , Polimorfismo de Nucleotídeo Único , Fator de Células-Tronco/genética , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/genética , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Expressão Gênica , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/etnologia , Neoplasias Embrionárias de Células Germinativas/patologia , Razão de Chances , Neoplasias Testiculares/etnologia , Neoplasias Testiculares/patologia
6.
Dis Markers ; 2019: 8298524, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565104

RESUMO

Malignant germ cell tumors (GCT) are the most common malignant tumors in young men between 18 and 40 years. The correct identification of histological subtypes, in difficult cases supported by immunohistochemistry, is essential for therapeutic management. Furthermore, biomarkers may help to understand pathophysiological processes in these tumor types. Two GCT cell lines, TCam-2 with seminoma-like characteristics, and NTERA-2, an embryonal carcinoma-like cell line, were compared by a quantitative proteomic approach using high-resolution mass spectrometry (MS) in combination with stable isotope labelling by amino acid in cell culture (SILAC). We were able to identify 4856 proteins and quantify the expression of 3936. 347 were significantly differentially expressed between the two cell lines. For further validation, CD81, CBX-3, PHF6, and ENSA were analyzed by western blot analysis. The results confirmed the MS results. Immunohistochemical analysis on 59 formalin-fixed and paraffin-embedded (FFPE) normal and GCT tissue samples (normal testis, GCNIS, seminomas, and embryonal carcinomas) of these proteins demonstrated the ability to distinguish different GCT subtypes, especially seminomas and embryonal carcinomas. In addition, siRNA-mediated knockdown of these proteins resulted in an antiproliferative effect in TCam-2, NTERA-2, and an additional embryonal carcinoma-like cell line, NCCIT. In summary, this study represents a proteomic resource for the discrimination of malignant germ cell tumor subtypes and the observed antiproliferative effect after knockdown of selected proteins paves the way for the identification of new potential drug targets.


Assuntos
Neoplasias Embrionárias de Células Germinativas/metabolismo , Proteoma , Neoplasias Testiculares/metabolismo , Técnicas de Cultura de Células/normas , Linhagem Celular Tumoral/classificação , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/genética , Testículo/metabolismo
7.
Folia Neuropathol ; 57(3): 227-238, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588709

RESUMO

INTRODUCTION: Germ cell tumours (GCTs) in the children comprise a group of tumours that originate from primordial germ cells but their pathogenesis is not clear. Intracranial GCTs represent a special subset of these paediatric neoplasms. Hedgehog (Hh) pathway gene status in GCTs is generally unexplored, while Hh signalling is involved in germ cell biology. MATERIAL AND METHODS: Comparative genomic profiling analysis with a microarray-comparative genomic hybridization (CGH) + single nucleotide polymorphism (SNP) technique in a group of intracranial paediatric GCTs was performed. The analysis included evaluation of genes being ligands, receptors, regulators, effectors, and targets of Hh signalling. RESULTS: Chromosomal aberrations were found in 62% of examined tumours, showing their heterogeneity. A number of private genomic imbalances were observed, but only a few recurrent ones. The most common numerical changes were trisomies 19, 21 and monosomies 13, 18 while the most frequent structural aberration was gain/amplification of the chromosome 12p. The analysis of the gene status of Hh network elements showed imbalances in a proportion of tumours. PTCH1, GLI2, IHH and ZIC2 gene aberrations occurred most frequently. Moreover, six tumours had various copy gains or losses of several other genes involved in the pathway, including HHIP, GLI1, GLI3, DHH, SHH, SMO, PTCH2, and several genes from the WNT group. Interestingly, four cases showed losses of pathway repressors, with parallel gains of activators in two of them. Correlations with patho-clinical tumour features were not found, most probably due to the heterogeneity of the examined limited group. CONCLUSIONS: Our results show few genomic alterations related to the Hh signalling pathway genes in paediatric intracranial GCTs. Further analysis of Hedgehog pathway alterations can potentially disclose its biological significance and define new prognostic factors and/or therapeutic targets for high-risk patients.


Assuntos
Neoplasias Encefálicas/genética , Proteínas Hedgehog/genética , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Encefálicas/metabolismo , Criança , Feminino , Proteínas Hedgehog/metabolismo , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/metabolismo , Transdução de Sinais/fisiologia
8.
Anticancer Res ; 39(9): 4911-4916, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519595

RESUMO

BACKGROUND/AIM: The occurrence of somatic transformation in germ cell tumour (GCT) is rare, with increased incidence in teratomatous tumours. The aim of this study was to understand the clinical outcomes of patients with metastatic GCT with somatic transformation. MATERIALS AND METHODS: A retrospective study was conducted in two tertiary cancer centres in London. Between 1998 and 2016, 30 cases of somatic transformation in GCT treated at the Mount Vernon Cancer Centre and St. Bartholomew's Hospital were identified. The median age at diagnosis was 34 years (range=18-56 years). The histological diagnosis at transformation was rhabdomyosarcoma, sarcomatoid yolk sac, sarcoma (non-specified), clear cell carcinoma, adenocarcinoma and primitive neuro ectodermal tumour (PNET). RESULTS: The 5-year survival rate of all patients was 47%, and that of patients with testicular primary (n=26 patients) was 37%. CONCLUSION: Somatic transformation component in testicular GCTs is generally considered to be an adverse prognostic factor, however, a reasonable 5-year overall survival rate (87.5%) was observed in patients who present with this at first diagnosis.


Assuntos
Transformação Celular Neoplásica/genética , Mutação , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/secundário , Neoplasias Testiculares/genética , Neoplasias Testiculares/secundário , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Suscetibilidade a Doenças , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/terapia , Retratamento , Análise de Sobrevida , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/terapia , Resultado do Tratamento , Adulto Jovem
9.
BMC Cancer ; 19(1): 802, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412792

RESUMO

BACKGROUND: To validate the utility of the chemokine ligand 12 (CXCL12) as prognostic marker in patients with localized and metastatic germ cell tumors (GCT). METHODS: CXCL12 expression was analyzed on a tissue microarray consisting of 750 tissue cores of different histological tumor components, Germ cell neoplasia in situ (GCNIS) and adjacent normal tissue of 263 testicular cancer patients using a semi-quantitative score. The association between CXCL12 expression and recurrence-free survival (RFS) as well as overall survival (OS) was assessed using Kaplan-Meier curves with log-rank tests. RESULTS: CXCL12 expression was absent in all seminomas but was found in 52 of 99 (52.5%) non-seminomas. Follow-up was available for 260 patients of which 36 (13.8%) recurred. In patients with stage 1 non-seminoma GCT, CXCL12 expression was not associated with higher risk of disease recurrence (p = 0.270). In contrast, post chemotherapy RFS of patients with metastatic non-seminoma and positive CXCL12 expression was significantly shorter compared to CXCL12 negative patients (p = 0.003). OS differences were not statistically different between patients with CXCL12 positive or negative tumors for either localized or metastatic disease. CONCLUSIONS: CXCL12 is almost exclusively expressed in non-seminoma. Pure seminoma, GCNIS and adjacent normal testicular tissue are CXCL12 negative. Our analysis suggests that patients with metastatic disease and a CXCL12-positive non-seminoma are at higher risk for disease recurrence after first-line chemotherapy and might thus be candidates for more intensive treatment and/or closer follow-up.


Assuntos
Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Recidiva Local de Neoplasia , Neoplasias Embrionárias de Células Germinativas/fisiopatologia , Neoplasias Testiculares/fisiopatologia , Adolescente , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Prognóstico , Seminoma/diagnóstico , Seminoma/fisiopatologia , Seminoma/terapia , Análise de Sobrevida , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismo , Adulto Jovem
10.
Nat Rev Cancer ; 19(9): 522-537, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31413324

RESUMO

Human germ cell tumours (GCTs) are derived from stem cells of the early embryo and the germ line. They occur in the gonads (ovaries and testes) and also in extragonadal sites, where migrating primordial germ cells are located during embryogenesis. This group of heterogeneous neoplasms is unique in that their developmental potential is in effect determined by the latent potency state of their cells of origin, which are reprogrammed to omnipotent, totipotent or pluripotent stem cells. Seven GCT types, defined according to their developmental potential, have been identified, each with distinct epidemiological and (epi)genomic features. Heritable predisposition factors affecting the cells of origin and their niches likely explain bilateral, multiple and familial occurrences of the different types of GCTs. Unlike most other tumour types, GCTs are rarely caused by somatic driver mutations, but arise through failure to control the latent developmental potential of their cells of origin, resulting in their reprogramming. Consistent with their non-mutational origin, even the malignant tumours of the group are characterized by wild-type TP53 and high sensitivity for DNA damage. However, tumour progression and the rare occurrence of treatment resistance are driven by embryonic epigenetic state, specific (sub)chromosomal imbalances and somatic mutations. Thus, recent progress in understanding GCT biology supports a comprehensive developmental pathogenetic model for the origin of all GCTs, and provides new biomarkers, as well as potential targets for treatment of resistant disease.


Assuntos
Biomarcadores Tumorais/genética , Epigênese Genética , Neoplasias Embrionárias de Células Germinativas/genética , Alelos , Animais , Biomarcadores Tumorais/metabolismo , Movimento Celular , Progressão da Doença , Desenvolvimento Embrionário , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Impressão Genômica , Genômica , Humanos , Cariotipagem , Masculino , Mutação , Neoplasias Embrionárias de Células Germinativas/metabolismo , Células-Tronco/metabolismo
11.
Biomed Pharmacother ; 117: 109090, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202174

RESUMO

Pannexin (Panx) plays a crucial role in several cellular processes such as immune cell death, cell proliferation, invasion, and migration, apoptosis, and autophagy. However, the role of Panx in regulating cell migration and invasion in testicular cancer remains to be elucidated. In the present study, we determined the correlation between Panx-1 channel function and migration and invasion in I-10 testicular cancer cells. Transwell and wound healing assays showed that inhibition of Panx-1 by carbenoxolone (CBX) and probenecid (PBN) attenuated the migration and invasion of testicular cancer cells in vitro. Moreover, knockdown of Panx-1 with short hairpin RNA (shRNA) remarkably decreased the migration and invasion ability of I-10 cells. In shRNA-transfected cells, extracellular ATP (released through Panx channel) was also found to be decreased. Similarly, overexpression of Panx-1 with mPanx-1 increased the migration and invasion ability of I-10 cells. Moreover, we found that in mPanx-1-transfected cells treated with U0126 (inhibitor of p-ERK1/2), the migration and invasion of I-10 cells were remarkably attenuated. Overall, increased Panx-1 promotes migration and invasion in testicular cancer cells, and the effect is probably be related with ERK1/2 kinase activity. Thus, Panx-1 can serve as a potential therapeutic target for the treatment of testicular cancer.


Assuntos
Movimento Celular/genética , Conexinas/genética , Sistema de Sinalização das MAP Quinases/genética , Invasividade Neoplásica/genética , Neoplasias Embrionárias de Células Germinativas/genética , Proteínas do Tecido Nervoso/genética , Neoplasias Testiculares/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Carbenoxolona/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Probenecid/farmacologia , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Neoplasias Testiculares/tratamento farmacológico
12.
Pediatr Blood Cancer ; 66(8): e27788, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31038288

RESUMO

Growing teratoma syndrome (GTS) is a condition in which mature teratoma with negative tumor markers arises at the site of a treated malignant germ cell tumor. Pathogenic variants in PTEN have been reported to cause autosomal dominant cancer predisposition syndromes and are associated with germ cell tumors. We report the association of a novel heterozygous pathogenic variant in PTEN and very early onset ovarian germ cell tumor complicated by GTS as well as overgrowth syndrome. This marks the youngest reported patient to have developed GTS following treatment of her primary malignant ovarian germ cell tumor.


Assuntos
Heterozigoto , Mutação , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/patologia , PTEN Fosfo-Hidrolase/genética , Teratoma/complicações , Pré-Escolar , Feminino , Humanos , Neoplasias Embrionárias de Células Germinativas/etiologia , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/genética , Prognóstico , Síndrome , Teratoma/genética
13.
Pediatr Blood Cancer ; 66(8): e27777, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31045322

RESUMO

BACKGROUND: Pediatric germ cell tumors (GCT) are rare and very heterogeneous neoplasms that show a high diversity in tumor biology and histology. The clinical behavior cannot be predicted based on morphology or immunohistochemistry. The aim of this study was to investigate a large number of pediatric GCT regarding chromosomal gains of 12p and 1q. METHODS: One hundred and eighty pediatric nonseminomatous GCT, that is, mature teratomas, immature teratomas, yolk sac tumors, and mixed germ cell tumors, from three age groups were evaluated for 1q and 12p gains by fluorescence in situ hybridization in tissue micro arrays. The results were correlated with tumor biology and clinical data. RESULTS: Eleven out of 143 GCT showed gains of 1q. In 29/157 GCT a gain of 12p was found. Prepubertal patients (≤6 years of age) more often displayed gains of 1q compared to pubertal/adolescent patients (11-17 years of age), whereas pubertal/adolescent patients showed gains of 12p most frequently. Twenty-one out of 155 patients suffered from relapse or metachronous disease. Patients with and without gains of 1q or 12p did not differ in frequency of these events. However, the likelihood of occurrence of these clinical events varied depending on the histological type of the tumor. CONCLUSION: The biological behavior of pediatric GCT depends more on the histological type of the tumor than on the genetic aberrations examined in this study. Gains of 1q and 12p are not suitable to predict the clinical outcome of GCT in childhood. Nevertheless, both genetic alterations might be used as biomarkers to distinguish different histological types of GCT and therefore could be of diagnostic value, especially in borderline cases.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 1/genética , Recidiva Local de Neoplasia/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Ovarianas/patologia , Teratoma/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Ovarianas/genética , Prognóstico , Estudos Retrospectivos , Teratoma/genética
14.
Genes (Basel) ; 10(5)2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083486

RESUMO

Although previous research identified candidate genetic polymorphisms associated with cisplatin nephrotoxicity, varying outcome definitions potentially contributed to the variability in the effect size and direction of this relationship. We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than one published study (SLC22A2 rs316019; ERCC1 rs11615 and rs3212986; ERCC2 rs1799793 and rs13181) and performed a replication analysis to confirm associations between these genetic polymorphisms and cisplatin nephrotoxicity using various outcome definitions. We included 282 germ cell testicular cancer patients treated with cisplatin from 2009-2014, aged >17 years recruited by the Canadian Pharmacogenomics Network for Drug Safety. Nephrotoxicity was defined using four grading tools: (1) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for acute kidney injury (AKI) or CTCAE-AKI; (2) adjusted cisplatin-induced AKI; (3) elevation of serum creatinine; and (4) reduction in the estimated glomerular filtration rate (eGFR). Significant associations were only found when using the CTCAE v4.03 definition: genotype CA of the ERCC1 rs3212986 was associated with decreased risk of cisplatin nephrotoxicity (ORadj = 0.24; 95% CI:0.08-0.70; p = 0.009) compared to genotype CC. In contrast, addition of allele A at SLC22A2 rs316019 was associated with increased risk (ORadj = 4.41; 95% CI:1.96-9.88; p < 0.001) while genotype AC was associated with a higher risk of cisplatin nephrotoxicity (ORadj = 5.06; 95% CI:1.69-15.16; p = 0.004) compared to genotype CC. Our study showed that different case definitions led to variability in the genetic risk ascertainment of cisplatin nephrotoxicity. Therefore, consensus on a set of clinically relevant outcome definitions that all such studies should follow is needed.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Cisplatino/efeitos adversos , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Transportador 2 de Cátion Orgânico/genética , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , Lesão Renal Aguda/genética , Adulto , Biomarcadores Farmacológicos , Creatinina/sangue , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Frequência do Gene , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Transportador 2 de Cátion Orgânico/metabolismo , Farmacogenética , Polimorfismo Genético , Estudos Retrospectivos , Neoplasias Testiculares/metabolismo , Proteína Grupo D do Xeroderma Pigmentoso/metabolismo
15.
Int J Surg Pathol ; 27(6): 619-623, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30983459

RESUMO

The incidence of bilateral testicular germ cell tumor (TGCT) is 1% to 5%. Despite the high rate of treatment success, resistance to chemotherapy has a detrimental effect. Some studies found MMR and BRAF gene mutations to be associated with chemotherapy resistance, which has not been found by others. However, the role of microsatellite instability (MSI) and BRAF mutations in bilateral disease has not been investigated. In this article, we studied the clinicopathologic characteristics and immunohistochemical expressions of MMR and BRAF in 13 patients with bilateral TGCT. Bilateral tumors were found in 4% of patients in our data. The mean ages at the first and subsequent diagnoses were 26.9 and 28.3 years, respectively. Eleven patients had metachronous disease; and the mean period between both tumors was 4.9 years. Six had mixed GCTs (MGCT) initially and later developed contralateral seminoma, 3 had bilateral MGCTs; 1 initially had pure embryonal carcinoma and subsequently MGCT and finally, 1 patient had initial seminoma and contralateral germ cell neoplasia in situ only. Of the patients with synchronous GCT, 1 had a MGCT and contralateral non-seminoma and 1 had seminoma and contralateral MGCT. In metachronous cases, 40% and 78% had an initial and subsequent stage of pT1, respectively. Hormonal and/or metastatic recurrence was observed in 30% of metachronous tumors. Six patients received chemotherapy, including patients with metastasis. No progression occurred after therapy. MLH1, PMS2, MSH2, and MSH6 staining was retained in all tumors. No BRAF staining was found. In conclusion, we found no association between bilateral TGCT and the MMR/MSI pathway and that subsequent metachronous tumors behaved much more indolently.


Assuntos
Reparo de Erro de Pareamento de DNA , Neoplasias Embrionárias de Células Germinativas/genética , Segunda Neoplasia Primária/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Testiculares/genética , Testículo/patologia , Adolescente , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Quimioterapia Adjuvante , Progressão da Doença , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/terapia , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/patologia , Orquiectomia , Proteínas Proto-Oncogênicas B-raf/análise , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/terapia , Testículo/cirurgia , Adulto Jovem
16.
Adv Anat Pathol ; 26(4): 241-245, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30950848

RESUMO

Testicular germ cell tumors are a diverse group of neoplasms, consisting of the prepubertal type 1 tumors, pure teratoma, and pure yolk sac tumor, the type 2 tumors, which are biologically malignant, preceded by germ cell neoplasia in situ, and harbor chromosome 12p abnormalities, and the type 3 tumor, spermatocytic tumor, which features chromosome 9p amplification. These arise in distinct clinical settings, and harbor distinct genetic abnormalities, immunohistochemical properties, and morphologic features. Here we have attempted to unify embryology, morphology, immunohistochemistry, and genetics in order to distill this fascinating group of neoplasms into what we hope is a useful framework for understanding their classification.


Assuntos
Biomarcadores Tumorais/genética , Tumor do Seio Endodérmico/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Testiculares/patologia , Aberrações Cromossômicas , Células Germinativas/patologia , Humanos , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/genética
17.
Artigo em Inglês | MEDLINE | ID: mdl-30970592

RESUMO

Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive genetic disorder resulting from maternally inherited or de novo mutations involving the androgen receptor gene, situated in the Xq11-q12 region. The diagnosis is based on the presence of female external genitalia in a 46, XY human individual, with normally developed but undescended testes and complete unresponsiveness of target tissues to androgens. Subsequently, pelvic ultrasound or magnetic resonance imaging (MRI) could be helpful in confirming the absence of Mullerian structures, revealing the presence of a blind-ending vagina and identifying testes. CAIS management still represents a unique challenge throughout childhood and adolescence, particularly regarding timing of gonadectomy, type of hormonal therapy, and psychological concerns. Indeed this condition is associated with an increased risk of testicular germ cell tumour (TGCT), although TGCT results less frequently than in other disorders of sex development (DSD). Furthermore, the majority of detected tumoral lesions are non-invasive and with a low probability of progression into aggressive forms. Therefore, histological, epidemiological, and prognostic features of testicular cancer in CAIS allow postponing of the gonadectomy until after pubertal age in order to guarantee the initial spontaneous pubertal development and avoid the necessity of hormonal replacement therapy (HRT) induction. However, HRT is necessary after gonadectomy in order to prevent symptoms of hypoestrogenism and to maintain secondary sexual features. This article presents differential clinical presentations and management in patients with CAIS to emphasize the continued importance of standardizing the clinical and surgical approach to this disorder.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Síndrome de Resistência a Andrógenos/tratamento farmacológico , Síndrome de Resistência a Andrógenos/genética , Androgênios/uso terapêutico , Terapia de Reposição Hormonal/métodos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome de Resistência a Andrógenos/fisiopatologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/fisiopatologia , Prognóstico , Neoplasias Testiculares/genética , Neoplasias Testiculares/fisiopatologia , Adulto Jovem
18.
PLoS One ; 14(3): e0213815, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870501

RESUMO

Testicular germ cell tumors (TGCTs) are unique amongst solid tumors in terms of the high cure rates using chemotherapy for metastatic disease. Nevertheless, TGCTs still kill approximately 400 men per year, at a median age of 30 years, in the United States. This young age of mortality dramatically amplifies the impact of these deaths for the patients and their often young families. Furthermore the high cure rate makes it difficult to conduct further clinical trials of non curable disease. TGCTs are characterized by a marked aneuploidy and the presence of gain of chromosomal region 12p. Genomic testing may offer the ability to identify potentially lethal TGCTs at the time of initial diagnosis. However sequencing based studies have shown a paucity of somatic mutations in TGCT genomes including those that drive refractory disease. Furthermore these studies may be limited by genetic heterogeneity in primary tumors and the evolution of sub populations during disease progression. Herein we applied a systematic approach combining DNA content flow cytometry, whole genome copy number and whole exome sequence analyses to interrogate tumor heterogeneity in primary and metastatic refractory TGCTs. We identified both known and novel somatic copy number aberrations (12p, MDM2, and RHBDD1) and mutations (XRCC2, PIK3CA, RITA1) including candidate markers for platinum resistance that were present in a primary tumor of mixed histology and that remained after tandem autologous stem cell transplant.


Assuntos
Biomarcadores Tumorais/genética , Cisplatino/farmacologia , Células Clonais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Genoma Humano , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/genética , Antineoplásicos/farmacologia , Células Clonais/efeitos dos fármacos , Células Clonais/metabolismo , Humanos , Masculino , Metástase Neoplásica , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/patologia , Células Tumorais Cultivadas
19.
Virchows Arch ; 474(6): 711-720, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30877382

RESUMO

By allelotyping analysis, we previously reported a putative progression pathway from germ cell neoplasia in situ (GCNIS) to seminoma, then to embryonal carcinoma in mixed-type testicular germ cell tumors (TGCTs), and detected that loss of heterozygosity events in seminoma components in mixed tumors were more frequent than those in pure seminomas. To elucidate a role of chromosomal instability in the progression of non-seminomatous germ cell tumor (NSGCT), we performed fluorescence in situ hybridization with centromeric probes for chromosomes 1, 7, 8, 12, 17, and X on a cohort of 52 TGCT cases with 103 histologically distinct components: 39 GCNIS lesions (16 and 23 in tumors with and without NSGCT components, respectively), 39 seminomas (27 as pure seminomas and 12 in mixed tumors), and 25 embryonal carcinomas. On a total component basis, both the mean copy number per tumor cell nucleus and the deviations from the modal number of all chromosomes examined significantly increased from GCNIS to seminoma, then to embryonal carcinoma with few exceptions. Seminoma components in mixed tumors showed a significantly greater extent of chromosomal instability in chromosomes 8 and 12 than pure seminomas, whereas no statistically significant difference was observed between GCNIS lesions with and without NSGCT components. These results suggest that not only aneuploidy, but also the cell-to-cell variation of chromosomal number is a sensitive indicator of chromosomal instability and would be implicated in the progression of NSGCT.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Embrionário/genética , Instabilidade Cromossômica/genética , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/genética , Adulto , Progressão da Doença , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Seminoma/genética , Seminoma/metabolismo , Neoplasias Testiculares/diagnóstico
20.
J Cancer Res Ther ; 15(Supplement): S60-S68, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30900623

RESUMO

Objective: To estimate association between androgen receptor (AR) gene polymorphisms and testicular germ cell tumor (TGCT) susceptibility. Materials and Methods: Systematic search of studies on the association between AR gene polymorphisms and TGCT susceptibility was conducted. Odds ratios and 95% confidence intervals were used to pool effect size. Results: For CAG repeat, no evidence was found for association between (>25 vs. ≤25), (>25 vs. 21-25), (<21 vs. 21-25), (others vs. 21-25), (>23 vs. ≤23), (<21 vs. ≥21), (<21 vs. ≥21)'s some subgroups and TGCT susceptibility, which showed stability. In (>24 vs. ≤24), (>24 vs. 21-24), (<21 vs. 21-24), and (others vs. 21-24) and almost all of their subgroups, increased TGCT risk was found without sensitivity analysis. For GGN, no statistical change of TGCT risk was found in (<23 vs. ≥23), (<23 vs. 23), which showed stability. For single nucleotide polymorphism (SNP) rs6152 G > A, rs1204038 G > A and rs2361634 A > G, no statistical change was found without sensitivity analysis. Conclusions: GGN repeat number <23 may not be associated with TGCTs susceptibility. However, there was insufficient data to fully confirm association in GGN repeat number >23, CAG repeat number, SNP rs6152, rs1204038, and rs2361634.


Assuntos
Predisposição Genética para Doença , Neoplasias Embrionárias de Células Germinativas/genética , Receptores Androgênicos/genética , Neoplasias Testiculares/genética , Repetições de Trinucleotídeos/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
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