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1.
Virchows Arch ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33009577

RESUMO

The morphological distinction between the various types of mucinous ovarian tumors has major prognostic implications but may be challenging. The aims of our study were to describe inter-observer reproducibility in the morphological diagnosis of mucinous ovarian tumors, to evaluate the clinical relevance of possible diagnostic discrepancies, and to identify molecular abnormalities correlated with the histological type. Seventy-nine ovarian mucinous borderline tumors (MOB) and either expansile or infiltrative carcinomas (MOC) were independently reviewed by two gynecological pathologists. Molecular analysis was performed in 32 cases. Concordance between the two pathologists was reached in 67 cases (k: 0.78). The main discrepancies (8/12) were the evaluation of nuclear grade 3 or that of microfoci (< 5 mm) of infiltrative-type carcinoma in an otherwise typical expansile MOC. Our follow-up analysis showed that infiltrative MOC had a lower overall survival (OS) (p < 0.0024) and progression-free survival (PFS) (p = 0.0060) as compared with MOB and expansile MOC. The presence of nuclear grade 3 or microfoci (< 5 mm) of infiltrative-type pattern of invasion in an otherwise typical expansile MOC did not alter the prognosis as compared with expansile MOC without these features, in terms of OS (p < 0.0028) and PFS (p = 0.0074). KRAS mutations were more frequent in MOB (71%), than in expansile (50%) and infiltrative MOC (14%). In contrast, the prevalence of TP53 mutation was lower in MOB (43%), than in expansile (58%) and infiltrative MOC (71%). Our results confirm that in MOC, the expansile pattern of invasion is associated with a better prognosis than extensive (> 5 mm) infiltrative-type pattern of invasion. No specific or sensitive molecular profile might help in the differential diagnosis of mucinous ovarian tumors.

2.
Cells ; 9(6)2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32575483

RESUMO

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive malignancy that occurs in young women, is characterized by recurrent loss-of-function mutations in the SMARCA4 gene, and for which effective treatments options are lacking. The aim of this study was to broaden the knowledge on this rare malignancy by reporting a comprehensive molecular analysis of an independent cohort of SCCOHT cases. We conducted Whole Exome Sequencing in six SCCOHT, and RNA-sequencing and array comparative genomic hybridization in eight SCCOHT. Additional immunohistochemical, Sanger sequencing and functional data are also provided. SCCOHTs showed remarkable genomic stability, with diploid profiles and low mutation load (mean, 5.43 mutations/Mb), including in the three chemotherapy-exposed tumors. All but one SCCOHT cases exhibited 19p13.2-3 copy-neutral LOH. SMARCA4 deleterious mutations were recurrent and accompanied by loss of expression of the SMARCA2 paralog. Variants in a few other genes located in 19p13.2-3 (e.g., PLK5) were detected. Putative therapeutic targets, including MAGEA4, AURKB and CLDN6, were found to be overexpressed in SCCOHT by RNA-seq as compared to benign ovarian tissue. Lastly, we provide additional evidence for sensitivity of SCCOHT to HDAC, DNMT and EZH2 inhibitors. Despite their aggressive clinical course, SCCOHT show remarkable inter-tumor homogeneity and display genomic stability, low mutation burden and few somatic copy number alterations. These findings and preliminary functional data support further exploration of epigenetic therapies in this lethal disease.

3.
Cancers (Basel) ; 12(3)2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32192091

RESUMO

Ovarian cancer (OC) is sensitive to upfront chemotherapy, which is likely attributable to defects in DNA damage repair (DDR). Unfortunately, patients relapse and the evolution of DDR competency are poorly described. We examined the expression of proposed effectors in homologous recombination (HR: RAD51, ATM, FANCD2), error-prone non-homologous end-joining (NHEJ: 53BP1), and base excision repair pathways (BER: PAR and PARP1) in a cohort of sequential OC samples obtained at diagnosis, after neoadjuvant chemotherapy (NACT), and/or at relapse from a total of 147 patients. Immunohistochemical (IHC) expression was quantified using the H-score (0-300), where H ≤ 10 defined negativity. Before NACT, a significant number of cases lacked the expression of some effectors: 60%, 60%, and 24% were PAR-, FANCD2-, or RAD51-negative, with a reassuringly similar proportion of negative biomarkers after NACT. In multivariate analysis, there was a poorer progression-free survival (PFS) and overall survival (OS) for cases with competent HR at diagnosis (PRE-NACT 53BP1-/RAD51+, hazard ratio (HR) 3.13, p = 0.009 and HR 2.78, p = 0.024) and after NACT (POST-NACT FANCD2+/RAD51+ HR 1.89, p = 0.05 and HR 2.38, p = 0.02; POST-NACT PARP-1+/RAD51+ HR 1.79, p = 0.038 and HR 2.04, p = 0.034), reflecting proficient DNA repair. Overall, HR-competent tumors appeared to have a dismal prognosis in comparison with tumors utilizing NHEJ, as assessed either at baseline or post-NACT. Accurate knowledge of the HR status during treatment is clinically important for the efficient timing of platinum-based and targeted therapies with poly(ADP-ribose) polymerase inhibitors (PARPi).

4.
Br J Cancer ; 122(4): 564-568, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31844183

RESUMO

BACKGROUND: Ovarian small cell carcinoma, hypercalcaemic type (SCCOHT) is a rare and lethal disease affecting young women. As histological diagnosis is challenging and urgent, there is a clear need for a robust diagnostic test. While mutations in the chromatin-remodelling gene, SMARCA4, appear to be typical, it may not be feasible routinely to be clinically relevant. METHODS: Previous studies have described the value of SMARCA4 IHC to differentiate SCCOHT from ovarian neoplasms (ON), with similar histologic appearances. We aimed to evaluate its clinical utility among a cohort of 44 SCCOHT and 94 rare ON frequently misdiagnosed as SCCOHT. RESULTS: Forty-three percent (16/36) of SCCOHT had been classified locally as non-SCCOHT confirming the diagnosis challenge. Sensitivity and specificity of SMARCA4 IHC were excellent at 88% and 94%, respectively. In a community setting with a much lower prevalence of the disease, estimated PPV is 40% while NPV remained high at 99%. Finally, among the 16 SCCOHT misclassified locally, SMARCA4 IHC testing would have resulted in corrected diagnosis in 88% of cases. CONCLUSIONS: SMARCA4 IHC is a highly sensitive, and specific test for the diagnosis of SCCOHT and is of huge clinical utility in providing a timely and accurate diagnosis of this challenging disease.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Pequenas/diagnóstico , DNA Helicases/biossíntese , Proteínas Nucleares/biossíntese , Neoplasias Ovarianas/diagnóstico , Fatores de Transcrição/biossíntese , Adulto , Carcinoma de Células Pequenas/metabolismo , DNA Helicases/análise , Feminino , Humanos , Hipercalcemia , Imuno-Histoquímica , Proteínas Nucleares/análise , Neoplasias Ovarianas/metabolismo , Sensibilidade e Especificidade , Fatores de Transcrição/análise
5.
Nat Commun ; 10(1): 558, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718512

RESUMO

Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16INK4a-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically.


Assuntos
Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/metabolismo , Ciclina D1/deficiência , DNA Helicases/metabolismo , Proteínas Nucleares/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Transcrição/metabolismo , Aminopiridinas/uso terapêutico , Animais , Benzimidazóis/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Imunoprecipitação da Cromatina , Ciclina D1/metabolismo , DNA Helicases/genética , Feminino , Humanos , Hipercalcemia/tratamento farmacológico , Hipercalcemia/metabolismo , Camundongos , Camundongos SCID , Proteínas Nucleares/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Piperazinas/uso terapêutico , Purinas/uso terapêutico , Piridinas/uso terapêutico , RNA Interferente Pequeno/genética , Fatores de Transcrição/genética
6.
Clin Cancer Res ; 25(3): 1087-1097, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30413523

RESUMO

PURPOSE: The elevated levels of somatic copy-number alterations (SCNAs) in a subset of high-risk endometrial cancers are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in endometrial cancers and its association with histopathologic and molecular characteristics. EXPERIMENTAL DESIGN: Fresh tumor tissue was prospectively collected from 36 endometrial cancers, and functional HRD was examined by the ability of replicating tumor cells to accumulate RAD51 protein at DNA double-strand breaks (RAD51 foci) induced by ionizing radiation. Genomic alterations were determined by next-generation sequencing and array comparative genomic hybridization/SNP array. The prevalence of BRCA-associated genomic scars, a surrogate marker for HRD, was determined in the The Cancer Genome Atlas (TCGA) endometrial cancer cohort. RESULTS: Most endometrial cancers included in the final analysis (n = 25) were of non-endometrioid (52%), grade 3 (60%) histology, and FIGO stage I (72%). HRD was observed in 24% (n = 6) of cases and was restricted to non-endometrioid endometrial cancers (NEEC), with 46% of NEECs being HRD compared with none of the endometrioid endometrial cancers (EEC, P = 0.014). All but 1 of the HRD cases harbored either a pathogenic BRCA1 variant or high somatic copy-number (SCN) losses of HR genes. Analysis of TCGA cases supported these results, with BRCA-associated genomic scars present in up to 48% (63/132) of NEEC versus 12% (37/312) of EEC (P < 0.001). CONCLUSIONS: HRD occurs in endometrial cancers and is largely restricted to non-endometrioid, TP53-mutant endometrial cancers. Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors.


Assuntos
Neoplasias do Endométrio/genética , Endométrio/metabolismo , Recombinação Homóloga/genética , Rad51 Recombinase/genética , Idoso , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Hibridização Genômica Comparativa , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Endométrio/efeitos dos fármacos , Endométrio/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Recombinação Homóloga/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Estudos Prospectivos , Rad51 Recombinase/metabolismo
7.
Mod Pathol ; 31(12): 1851-1861, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29955143

RESUMO

The TransPORTEC consortium previouslclassified high-risk endometrial cancer including poor-risk histologies such as clear cells, into four molecular subtypes "POLE mutated," "microsatellite unstable," "TP53 mutated," and "no specific molecular profile." We evaluated whether DNA damage response biomarkers could further refine this high-risk tumors classification, in particular the heterogeneous "no specific molecular profile" and "TP53 mutated" subsets recently qualified as poor prognosis in high-risk endometrial cancer. DNA damage response biomarkers including proteins involved in DNA damage (δ-H2AX), homologous recombination (RAD51), regulators of error-prone Non Homologous End-Joining (DNA-pk, FANCD2), and PARP-1 were evaluated in 116 high-risk tumors by immunohistochemistry. CD8 and PD-1 expression by immunochemistry and mutation analyses were performed previously. Survival outcome were calculated using Kaplan-Meier and Log-rank test. None of the DNA damage response biomarkers alone were prognostic. However markers were informative within molecular subsets. Among the "no specific molecular profile" subset, δ-H2AX+ was significantly predictive of poor disease free survival (Hazard Ratio = 2.56; p = 0.026), and among "TP53 mutated," a DNA-pk+/FANCD2- profile (favouring error-prone Non Homologous End-Joining) predicted worst disease free survival (Hazard Ratio = 4.95; p = 0.009) resulting in five distinct prognostic subgroups from best to worst prognosis: group1 "POLE mutated/Microsatellite unstable" > group2 "no specific molecular profile with no DNA damage" > group3 "TP53 mutated/Non Homologous End-Joining negative" > group4 "no specific molecular profile with high DNA damage" > group5 "TP53 mutated/Non Homologous End-Joining positive"; p = 0.0002). Actionable targets were also different among subsets. Group3 had significantly higher infiltration of PD-1+ immune cells (p = 0.003), segregating with group1. Group2 had frequent PI3K pathway mutations and ER positivity. While group5, with the worst prognosis, had high DNA damage and PARP-1 expression providing a rationale for PARP inhibition. Our findings have refined the TransPORTEC prognostic classification of high-risk endometrial cancer into five distinct subgroups by integrating DNA damage response biomarkers and identified molecular subtype-specific therapeutic strategies.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Dano ao DNA/genética , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco
8.
Oncotarget ; 9(5): 6144-6155, 2018 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-29464061

RESUMO

Lactotroph adenoma, also called prolactinoma, is the most common pituitary tumor but little is known about its pathogenesis. Mouse models of prolactinoma can be useful to better understand molecular mechanisms involved in abnormal lactotroph cell proliferation and secretion. We have previously developed a prolactin receptor deficient (Prlr-/- ) mouse, which develops prolactinoma. The present study aims to explore the natural history of prolactinoma formation in Prlr-/- mice, using hormonal, radiological, histological and molecular analyses to uncover mechanisms involved in lactotroph adenoma development. Prlr-/- females develop large secreting prolactinomas from 12 months of age, with a penetrance of 100%, mimicking human aggressive densely granulated macroprolactinoma, which is a highly secreting subtype. Mean blood PRL measurements reach 14 902 ng/mL at 24 months in Prlr-/- females while PRL levels were below 15 ng/mL in control mice (p < 0.01). By comparing pituitary microarray data of Prlr-/- mice and an estrogen-induced prolactinoma model in ACI rats, we pinpointed 218 concordantly differentially expressed (DE) genes involved in cell cycle, mitosis, cell adhesion molecules, dopaminergic synapse and estrogen signaling. Pathway/gene-set enrichment analyses suggest that the transcriptomic dysregulation in both models of prolactinoma might be mediated by a limited set of transcription factors (i.e., STAT5, STAT3, AhR, ESR1, BRD4, CEBPD, YAP, FOXO1) and kinases (i.e., JAK2, AKT1, BRAF, BMPR1A, CDK8, HUNK, ALK, FGFR1, ILK). Our experimental results and their bioinformatic analysis provide insights into early genomic changes in murine models of the most frequent human pituitary tumor.

10.
Int J Cancer ; 143(1): 8-15, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29218796

RESUMO

Over the last decade, increasing evidence highlights the role of the host immune system in the control of tumor growth and the prognostic implications of tumor infiltrating lymphocytes (TILs) in ovarian cancer. Most data support a better prognosis with accumulation of CD3+ and CD8 + TILs and a poor outcome associated with increased regulatory T cells. However, only a small number of studies have focused on the effect of neoadjuvant chemotherapy (NACT) on the tumor immune microenvironment. This review will provide an update on the prognostic value of TIL subpopulations at diagnosis and a comprehensive overview of the recent studies evaluating the impact of neoadjuvant chemotherapy on TILs and their relationship to clinical outcome in advanced ovarian cancer. This information could help in future investigations of immunotherapy as maintenance following primary treatment.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Animais , Carboplatina/uso terapêutico , Carcinoma Epitelial do Ovário/imunologia , Feminino , Humanos , Terapia Neoadjuvante/métodos , Neoplasias Ovarianas/imunologia , Paclitaxel/uso terapêutico , Prognóstico , Microambiente Tumoral/efeitos dos fármacos
11.
Bull Cancer ; 104(12): 1001-1012, 2017 Dec.
Artigo em Francês | MEDLINE | ID: mdl-29031505

RESUMO

Endometrial cancer is the fourth cause of cancer in women in France and is the second most common cancer of the gynecologic cancer after breast cancer with 7275 new cases in 2012. The incidence of this neoplasm tends to increase with population aging, diabetes and obesity's augmentation. In rare cases, a hereditary factor has been described: Lynch's syndrome. The therapeutic management of the patient depends on the endometrial biopsy which specifies the histological type and the histo-prognostic grade as well as the MRI which allow the tumor staging. Within the last decade, improvement in technologies such as genomic, transcriptomic and histological analyses, allowed the establishment of new and finer classifications of endometrial carcinomas. The latest classification proposed by The Cancer Genomic Atlas (TCGA), has been made routinely applicable through the international consortium TransPORTEC. It consists of 4 groups listed from good to poor prognosis: (1) ultra-mutated "POLE"; (2) hyper-mutated "MSI"; (3) low copy number "NSMP" and (4) high number of copies "TP53 mutated" (serous-like). This integrated characterization combined with mutational data opens new opportunities for therapeutic strategies.


Assuntos
Carcinoma Endometrioide , Neoplasias do Endométrio , Tumor Misto Maligno , Biópsia , Carcinoma Endometrioide/classificação , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/terapia , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Endométrio/patologia , Feminino , Humanos , Imunoterapia/métodos , Tumor Misto Maligno/classificação , Tumor Misto Maligno/genética , Tumor Misto Maligno/patologia , Tumor Misto Maligno/terapia , Terapia de Alvo Molecular , Prognóstico , Fatores de Risco
12.
Bull Cancer ; 104(11): 971-980, 2017 Nov.
Artigo em Francês | MEDLINE | ID: mdl-29054544

RESUMO

The demonstration of frequent defects in the DNA damage response in high grade ovarian cancer has paved the way for a new therapeutic approach aimed at exploiting this unique vulnerability. The efficacy of poly (ADP) ribose polymerase inhibitors (PARPi) in patients with homologous recombination (HR) DNA repair deficient ovarian cancer (OC) resulting from a BRCA1/2 mutation has provided the proof of concept for synthetic lethality. Thus, olaparib is now approved by the EMA as maintenance therapy after response to a platinum regimen for patients with recurrent, platinum-sensitive, high-grade serous, BRCA1/2-mutated ovarian cancer. Furthermore, several recent trials in OC have demonstrated that the benefit of PARPi may not be limited to patients with BRCA mutations. These data, combined with genomic studies suggesting that a significant proportion of OC may harbor somatic and germline alterations in other HR genes open huge perspectives for exploiting DNA repair as a therapeutic strategy. The current priorities are to (i) determine whether new biomarkers of homologous recombination deficiency may identify the BRCA wild-type subset likely to derive benefit from PARPi; (ii) to determine whether the efficacy of PARPi can be improved by combinatorial strategies (with chemotherapy, radiotherapy, immunotherapy, anti-angiogenesis or DNA repair inhibitors) and (iii) to develop new approaches exploiting DNA repair deficiencies in ovarian and other gynecological tumors.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose , Terapia Combinada , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/genética , DNA de Neoplasias/efeitos da radiação , Sinergismo Farmacológico , Feminino , Genes BRCA1 , Genes BRCA2 , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/genética , Humanos , Quimioterapia de Manutenção , Mutação , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/fisiologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/terapia , Inibidores de Fosfoinositídeo-3 Quinase , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Reparo de DNA por Recombinação
13.
Curr Opin Oncol ; 28(5): 404-11, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27455135

RESUMO

PURPOSE OF REVIEW: The proven activity of poly ADP ribose polymerase (PARP) inhibitors in BRCA-mutated homologous recombination deficient (HRD) ovarian cancer has led to the availability to patients with ovarian cancer of the first targeted therapy with an associated predictive biomarker. Our focus has recently turned towards expanding the clinical utility of PARP inhibitors beyond BRCA mutated ovarian cancer, and to a search for novel targets within DNA damage response (DDR). RECENT FINDINGS: Early trials in unselected patients with ovarian cancer showed responses to PARP inhibition in BRCA-wildtype ovarian cancer, and recent genomic studies have demonstrated that germline or somatic aberrations in other homologous recombination genes are present in a significant proportion of ovarian cancers. In addition, PARP inhibition may be of value in molecularly defined subsets of endometrial or cervical cancers. Novel DDR inhibitors such as ATR, ATM, WEE1 or DNA-PK inhibitors are also being tested in patients. Finally, combinatorial strategies of DDR inhibitors with antiangiogenic agents, phosphoinositide 3-kinase inhibitors or immunotherapies may further increase therapeutic efficacy. SUMMARY: In the future, patients with gynaecological malignancies may be rationally selected for PARP inhibition on the basis of comprehensive evaluation of homologous recombination genomic alterations, or HRD assays. Furthermore, novel DDR inhibitors have the potential to expand the repertoire of therapeutic options available to these patients.


Assuntos
Dano ao DNA , Neoplasias dos Genitais Femininos/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Feminino , Neoplasias dos Genitais Femininos/enzimologia , Humanos , Terapia de Alvo Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
14.
Hum Mol Genet ; 24(23): 6687-98, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26362254

RESUMO

Juvenile granulosa cell tumors (JGCTs) of the ovary are pediatric neoplasms representing 5% of all granulosa cell tumors (GCTs). Most GCTs are of adult type (AGCTs) and bear a mutation in the FOXL2 gene. The molecular basis of JGCTs is poorly understood, although mutations in the GNAS gene have been reported. We have detected in-frame duplications within the oncogene AKT1 in >60% of the JGCTs studied. Here, to evaluate the functional impact of these duplications and the existence of potential co-driver alterations, we have sequenced the transcriptome of four JGCTs and compared them with control transcriptomes. A search for gene variants detected only private alterations probably unrelated with tumorigenesis, suggesting that tandem duplications are the best candidates to underlie tumor formation in the absence of GNAS alterations. We previously showed that the duplications were specific to JGCTs. However, the screening of eight AGCTs samples without FOXL2 mutation showed the existence of an AKT1 duplication in one case, also having a stromal luteoma. The analysis of RNA-Seq data pinpointed a series of differentially expressed genes, involved in cytokine and hormone signaling and cell division-related processes. Further analyses pointed to the existence of a possible dedifferentiation process and suggested that most of the transcriptomic dysregulation might be mediated by a limited set of transcription factors perturbed by AKT1 activation. Finally, we show that commercially available AKT inhibitors can modulate the in vitro activity of various mutated forms. These results shed light on the pathogenesis of JGCTs and provide therapeutic leads for a targeted treatment.


Assuntos
Tumor de Células da Granulosa/genética , Mutação , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas c-akt/genética , Adolescente , Divisão Celular/genética , Criança , Pré-Escolar , Citocinas , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Tumor de Células da Granulosa/metabolismo , Hormônios , Humanos , Lactente , Recém-Nascido , Neoplasias Ovarianas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/genética
15.
Nat Genet ; 47(10): 1200-5, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26343384

RESUMO

While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4-mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs), SMARCB1-inactivated malignant rhabdoid tumors (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4-deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of 'SMARCA4-deficient thoracic sarcomas' as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.


Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Sarcoma/genética , Neoplasias Torácicas/genética , Fatores de Transcrição/genética , Transcrição Genética , Adulto , Humanos
16.
EBioMedicine ; 2(5): 421-31, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26137586

RESUMO

BACKGROUND: Ovarian granulosa cell tumors are the most common sex-cord stromal tumors and have juvenile (JGCTs) and adult forms. In a previous study we reported the occurrence of activating somatic mutations of Gαs, which transduces mitogenic signals, in 30% of the analyzed JGCTs. METHODS: We have searched for alterations in other proteins involved in ovarian mitogenic signaling. We focused on the PI3K-AKT axis. As we found mutations in AKT1, we analyzed the subcellular localization of the mutated proteins and performed functional explorations using Western-blot and luciferase assays. FINDINGS: We detected in-frame duplications affecting the pleckstrin-homology domain of AKT1 in more than 60% of the tumors occurring in girls under 15 years of age. The somatic status of the mutations was confirmed when peritumoral DNA was available. The JGCTs without duplications carried point mutations affecting highly conserved residues. Several of these substitutions were somatic lesions. The mutated proteins carrying the duplications had a non-wild-type subcellular distribution, with a marked enrichment at the plasma membrane. This led to a striking degree of AKT1 activation demonstrated by a strong phosphorylation level and by reporter assays. INTERPRETATION: Our study incriminates somatic mutations of AKT1 as a major event in the pathogenesis of JGCTs. The existence of AKT inhibitors currently tested in clinical trials opens new perspectives for targeted therapies for these tumors, which are currently treated with standard non-specific chemotherapy protocols.


Assuntos
Duplicação Gênica/genética , Tumor de Células da Granulosa/enzimologia , Tumor de Células da Granulosa/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fases de Leitura/genética , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular Tumoral , Criança , Pré-Escolar , Ativação Enzimática/genética , Feminino , Células HeLa , Humanos , Dados de Sequência Molecular , Proteínas Mutantes/metabolismo , Fosforilação , Mutação Puntual/genética , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/química , Frações Subcelulares/metabolismo
17.
Chin J Cancer ; 34(1): 4-16, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25556614

RESUMO

The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer, including ovarian cancer (OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin (mTOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective mTOR complex-1 (mTORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual mTORC1/mTORC2, Akt, and PI3K inhibitors. Although it is likely that inhibition of the PI3K/Akt/mTOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and/or phosphatase and tensin homolog (PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3K signaling network, PI3K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3K pathway in OC and provide an up-to-date review of clinical trials of novel PI3K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.


Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais , Serina-Treonina Quinases TOR/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/fisiologia
18.
Elife ; 32014 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-25369636

RESUMO

FOXL2 is a lineage determining transcription factor in the ovary, but its direct targets and modes of action are not fully characterized. In this study, we explore the targets of FOXL2 and five nuclear receptors in murine primary follicular cells. We found that FOXL2 is required for normal gene regulation by steroid receptors, and we show that estrogen receptor beta (ESR2) is the main vector of estradiol signaling in these cells. Moreover, we found that FOXL2 directly modulates Esr2 expression through a newly identified intronic element. Interestingly, we found that FOXL2 repressed the testis-determining gene Sox9 both independently of estrogen signaling and through the activation of ESR2 expression. Altogether, we show that FOXL2 mobilizes estrogen signaling to establish a coherent feed-forward loop repressing Sox9. This sheds a new light on the role of FOXL2 in ovarian maintenance and function.


Assuntos
Estrogênios/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Células da Granulosa/citologia , Células da Granulosa/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Estradiol/farmacologia , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Proteína Forkhead Box L2 , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Genoma , Células da Granulosa/efeitos dos fármacos , Camundongos , Receptores Citoplasmáticos e Nucleares/metabolismo , Sequências Reguladoras de Ácido Nucleico/genética , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
19.
J Mol Endocrinol ; 52(1): R17-33, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24049064

RESUMO

Forkhead box L2 (FOXL2) is a gene encoding a forkhead transcription factor preferentially expressed in the ovary, the eyelids and the pituitary gland. Its germline mutations are responsible for the blepharophimosis ptosis epicanthus inversus syndrome, which includes eyelid and mild craniofacial defects associated with primary ovarian insufficiency. Recent studies have shown the involvement of FOXL2 in virtually all stages of ovarian development and function, as well as in granulosa cell (GC)-related pathologies. A central role of FOXL2 is the lifetime maintenance of GC identity through the repression of testis-specific genes. Recently, a highly recurrent somatic FOXL2 mutation leading to the p.C134W subtitution has been linked to the development of GC tumours in the adult, which account for up to 5% of ovarian malignancies. In this review, we summarise data on FOXL2 modulators, targets, partners and post-translational modifications. Despite the progresses made thus far, a better understanding of the impact of FOXL2 mutations and of the molecular aspects of its function is required to rationalise its implication in various pathophysiological processes.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Ovário/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Feminino , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Células da Granulosa/citologia , Células da Granulosa/metabolismo , Humanos , Folículo Ovariano/fisiologia , Ovário/fisiologia , Processos de Determinação Sexual/fisiologia
20.
PLoS One ; 8(4): e60451, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23593221

RESUMO

The rabbit is an attractive species for the study of gonad differentiation because of its 31-day long gestation, the timing of female meiosis around birth and the 15-day delay between gonadal switch and the onset of meiosis in the female. The expression of a series of genes was thus determined by qPCR during foetal life until adulthood, completed by a histological analysis and whenever possible by an immunohistological one. Interesting gene expression profiles were recorded. Firstly, the peak of SRY gene expression that is observed in early differentiated XY gonads in numerous mammals was also seen in the rabbit, but this expression was maintained at a high level until the end of puberty. Secondly, a peak of aromatase gene expression was observed at two-thirds of the gestation in XX gonads as in many other species except in the mouse. Thirdly, the expression of STRA8 and DMC1 genes (which are known to be specifically expressed in germ cells during meiosis) was enhanced in XX gonads around birth but also slightly and significantly in XY gonads at the same time, even though no meiosis occurs in XY gonad at this stage. This was probably a consequence of the synchronous strong NANOS2 gene expression in XY gonad. In conclusion, our data highlighted some rabbit-specific findings with respect to the gonad differentiation process.


Assuntos
Diferenciação Celular , Ovário/citologia , Ovário/embriologia , Testículo/citologia , Testículo/embriologia , Animais , Biomarcadores/metabolismo , Feminino , Feto/citologia , Feto/embriologia , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Meiose , Camundongos , Ovário/metabolismo , Óvulo/citologia , Óvulo/metabolismo , Puberdade , Coelhos , Especificidade da Espécie , Espermatozoides/citologia , Espermatozoides/metabolismo , Testículo/metabolismo , Tretinoína/metabolismo
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