Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.896
Filtrar
1.
DNA Cell Biol ; 40(4): 618-628, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33751900

RESUMO

The expressions and roles of protein inhibitor of activated STAT (PIAS) proteins, a group of proteins with STAT inhibition and SUMOylation E3 ligase activity, are rarely revealed in endometrial cancer (EC). In this study, we analyzed the expressions of PIASs and their relationships with clinical features by mining online data through web servers, including UALCAN and Gene Expression Profiling Interactive Analysis (GEPIA) in EC. The expressions of PIASs in EC tissues were further validated by immunohistochemistry (IHC). The online analyses revealed only PIAS1 was consistently downregulated both at mRNA and protein level in EC, which was validated by the IHC. Subsequently, the mechanism of PIAS1 downregulation was explored with online tools like UALCAN, cBioPortal, LinkedOmics, and the Encyclopedia of RNA Interactomes (ENCORI). The results indicated that the mutation rate of PIAS1 was extremely low and not associated with PIAS1 expression. The promoter methylation level of PIAS1 was comparable between normal and EC tissues. miR-182-5p and miR-96-5p with negative association with PIAS1 in EC were predicted to target PIAS1. Dual luciferase reporter assay confirmed miR-182-5p and miR-96-5p could target PIAS1 in EC. MiR-182-5p and miR-96-5p inhibitors could upregulate PIAS1 in EC cells. Moreover, ectopic PIAS1 expression and STAT3 inhibitor treatment significantly inhibited STAT3's activity and the levels of miR-182-5p and miR-96-5p in EC cells. Collectively, our findings revealed PIAS1 was downregulated in EC, which was caused by upregulation of miR-182-5p and miR-96-5p, and PIAS1 downregulation further activated STAT3 and increased the expression of miR-182-5p and miR-96-5p, confirming miR-182-5p and miR-96-5p mediated the negative feedback regulatory loop between PIAS1 and STAT3 in EC.


Assuntos
Neoplasias do Endométrio/genética , MicroRNAs/genética , Adulto , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MicroRNAs/metabolismo , Proteínas Inibidoras de STAT Ativados/genética , Proteínas Inibidoras de STAT Ativados/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo
2.
Virchows Arch ; 478(2): 153-190, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33604759

RESUMO

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.


Assuntos
Carcinoma/terapia , Neoplasias do Endométrio/terapia , Oncologia/normas , Biomarcadores Tumorais/genética , Biópsia/normas , Carcinoma/genética , Carcinoma/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Medicina Baseada em Evidências/normas , Feminino , Humanos , Técnicas de Diagnóstico Molecular/normas , Estadiamento de Neoplasias/normas , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Resultado do Tratamento
3.
Am J Epidemiol ; 190(2): 230-238, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524116

RESUMO

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.


Assuntos
Estatura , Neoplasias Colorretais/epidemiologia , Neoplasias do Endométrio/epidemiologia , Adulto , Fatores Etários , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores Sexuais
4.
Int J Mol Sci ; 21(24)2020 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352687

RESUMO

Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in BRCA1 and BRCA2 genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about BRCA gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without BRCA germline mutations. We identified 20/88 (22.7%) EOCs showing BRCA promoter methylation, including 17/88 (19.3%) in BRCA1 and 4/86 (4.6%) in BRCA2 promoters, one of which showing concomitant BRCA1 methylation. Mean methylation levels were 49.6% and 45.8% for BRCA1 and BRCA2, respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive BRCA methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of BRCA genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline BRCA-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with BRCA methylation, even without BRCA mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic BRCA methylation of PARP-therapy response.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Metilação de DNA , Mutação , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Adulto , Idoso , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Prognóstico , Regiões Promotoras Genéticas , Estudos Retrospectivos , Taxa de Sobrevida
5.
PLoS One ; 15(12): e0244558, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33378353

RESUMO

OBJECTIVE: DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in melanoma, bladder, and prostate cancer. Loss of DACH1 expression is associated with poor prognostic features and reduced overall survival in uterine cancer. In this study, we utilized the Oncology Research Information Exchange Network (ORIEN) Avatar database to determine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky population. METHODS: We obtained clinical and genomic data for 65 patients with endometrial cancer from the Markey Cancer Center (MCC). We examined the clinical attributes of the cancers by DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). RESULTS: Kentucky women with endometrial cancer had an increased frequency of DACH1 mutations (12/65 patients, 18.5%) compared to The Cancer Genome Atlas (TCGA) endometrial cancer population (25/586 patients, 3.8%) with p-value = 1.04E-05. DACH1 mutations were associated with increased tumor mutation count in both TCGA (median 65 vs. 8972, p-value = 7.35E-09) and our Kentucky population (490 vs. 2160, p-value = 6.0E-04). DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (24 vs. 6.02, p-value = 4.29E-05). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, and PMS2. DACH1 mutations were not associated with an increase in microsatellite instability at MCC (MSI-H) (p-value = 0.1342). CONCLUSIONS: DACH1 mutations are prevalent in Kentucky patients with endometrial cancer. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 may be a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers.


Assuntos
Neoplasias do Endométrio/patologia , Proteínas do Olho/genética , Taxa de Mutação , Fatores de Transcrição/genética , Idoso , DNA Polimerase II/genética , Bases de Dados Genéticas , Neoplasias do Endométrio/genética , Feminino , Humanos , Kentucky , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Gradação de Tumores , Proteínas de Ligação a Poli-ADP-Ribose/genética , Prevalência , Prognóstico , Sistema de Registros , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
7.
PLoS Med ; 17(9): e1003263, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32941469

RESUMO

BACKGROUND: Lynch syndrome (LS) predisposes to endometrial cancer (EC), colorectal cancer, and other cancers through inherited pathogenic variants affecting mismatch-repair (MMR) genes. Diagnosing LS in women with EC can reduce subsequent cancer mortality through colonoscopic surveillance and aspirin chemoprevention; it also enables cascade testing of relatives. A growing consensus supports LS screening in EC; however, the expected proportion of test positives, and optimal testing strategy is uncertain. Previous studies from insurance-based healthcare systems were limited by narrow selection criteria, failure to apply reference standard tests consistently, and poor conversion to definitive testing. The aim of this study was to establish the prevalence of LS and the diagnostic accuracy of LS testing strategies in an unselected EC population. METHODS AND FINDINGS: This was a prospective cross-sectional study carried out at a large United Kingdom gynaecological cancer centre between October 2015 and January 2017. Women diagnosed with EC or atypical hyperplasia (AH) were offered LS testing. Tumours underwent MMR immunohistochemistry (IHC), microsatellite instability (MSI), and targeted MLH1-methylation testing. Women <50 years, with strong family histories and/or indicative tumour molecular features, underwent MMR germline sequencing. Somatic MMR sequencing was performed when indicative molecular features were unexplained by LS or MLH1-hypermethylation. The main outcome measures were the prevalence of LS in an unselected EC population and the diagnostic accuracy of clinical and tumour testing strategies for risk stratifying women with EC for MMR germline sequencing. In total, 500 women participated in the study; only 2 (<1%) declined. Germline sequencing was indicated and conducted for 136 and 135 women, respectively. A total of 16/500 women (3.2%, 95% CI 1.8% to 5.1%) had LS, and 11 more (2.2%) had MMR variants of uncertain significance. Restricting testing to age <50 years, indicative family history (revised Bethesda guidelines or Amsterdam II criteria) or endometrioid histology alone would have missed 9/16 (56%), 8/13 (62%) or 9/13 (69%), and 5/16 (31%) cases of LS, respectively. In total 132/500 tumours were MMR deficient by IHC of which 83/132 (63%) had MLH1-hypermethylation, and 16/49 (33%) of the remaining patients had LS (16/132 with MMR deficiency, 12%). MMR-IHC with targeted MLH1-methylation testing was more discriminatory for LS than MSI with targeted methylation testing, with 100% versus 56.3% (16/16 versus 9/16) sensitivity (p = 0.016) and equal 97.5% (468/484) specificity; 64% MSI-H and 73% MMR deficient tumours unexplained by LS or MLH1-hypermethylation had somatic MMR mutations. The main limitation of the study was failure to conduct MMR germline sequencing for the whole study population, which means that the sensitivity and specificity of tumour triage strategies for LS detection may be overestimated, although the risk of LS in women with no clinical or tumour predictors is expected to be extremely low. CONCLUSIONS: In this study, we observed that age, family history, and histology are imprecise clinical correlates of LS-EC. IHC outperformed MSI for tumour triage and reliably identified both germline and somatic MMR mutations. The 3.2% proportion of LS-EC is similar to colorectal cancer, supporting unselected screening of EC for LS.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Detecção Precoce de Câncer/métodos , Neoplasias do Endométrio/genética , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Estudos Transversais , Metilação de DNA/genética , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/diagnóstico , Feminino , Testes Genéticos/métodos , Humanos , Imuno-Histoquímica , Programas de Rastreamento/métodos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Reino Unido
8.
PLoS One ; 15(9): e0238477, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32877461

RESUMO

Somatic copy number alterations (CNA) are common in endometrial serous carcinoma (ESC). We used the Tumor Cancer Genome Atlas Pan Cancer dataset (TCGA Pan Can) to explore the impact of somatic CNA and gene expression levels (mRNA) of cancer-related genes in ESC. Results were correlated with clinico-pathologic parameters such as age of onset, disease stage, progression-free survival (PFS) and overall survival (OS) (n = 108). 1,449 genes with recurrent somatic CNA were identified, observed in 10% or more tumor samples. Somatic CNA and mRNA expression levels were highly correlated (r> = 0.6) for 383 genes. Among these, 45 genes were classified in the Tier 1 category of Cancer Genome Census-Catalogue of Somatic Mutations in Cancer. Eighteen of 45 Tier 1 genes had highly correlated somatic CNA and mRNA expression levels including ARNT, PIK3CA, TBLXR1, ASXL1, EIF4A2, HOOK3, IKBKB, KAT6A, TCEA1, KAT6B, ERBB2, BRD4, KEAP1, PRKACA, DNM2, SMARCA4, AKT2, SS18L1. Our results are in agreement with previously reported somatic CNA for ERBB2, BRD4 and PIK3C in ESC. In addition, AKT2 (p = 0.002) and KAT6A (p = 0.015) amplifications were more frequent in tumor samples from younger patients (<60), and CEBPA (p = 0.028) and MYC (p = 0.023) amplifications were more common with advanced (stage III and IV) disease stage. Patients with tumors carrying KAT6A and MYC amplifications had shorter PFS and OS. The hazard ratio (HR) of KAT6A was 2.82 [95 CI 1.12-7.07] for PFS and 3.87 [95 CI 1.28-11.68] for OS. The HR of MYC was 2.25 [95 CI 1.05-4.81] and 2.62[95 CI 1.07-6.41] for PFS and OS, respectively.


Assuntos
Neoplasias do Endométrio/genética , Histona Acetiltransferases/genética , Biomarcadores Tumorais/genética , Classe I de Fosfatidilinositol 3-Quinases , Cistadenocarcinoma Seroso/genética , Variações do Número de Cópias de DNA/genética , DNA Helicases , Bases de Dados Genéticas , Intervalo Livre de Doença , Neoplasias do Endométrio/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Histona Acetiltransferases/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch , Mutação , Fator 2 Relacionado a NF-E2 , Proteínas Nucleares/genética , Oncogenes , Neoplasias Ovarianas/patologia , Prognóstico , Intervalo Livre de Progressão , Fatores de Transcrição , Transcriptoma/genética
9.
Life Sci ; 258: 118231, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791150

RESUMO

AIMS: Cancer Stem Cells (CSCs) refers to heterogeneous tumor cells retaining the abilities of self-renewal and differentiation. This study used mRNAsi, which is an index to describe the similarity between tumor cells and CSCs, to define genes involved in endometrial carcinoma. MATERIALS AND METHODS: The mRNA expression profiles of 552 tumor samples and 23 non-tumor samples were calculated for differentially expressed genes. WGCNA was utilized to construct gene co-expression networks and classify screened genes into different modules. Univariate and multivariate Cox regression models were performed to identify and construct the prognostic model. Time-dependent receiver operating characteristic (ROC), Kaplan-Meier curve, multivariate Cox regression analysis, and nomogram were used to assess the prognostic capacity of the six-gene signature. The screened genes were further validated by GEO (GSE17025) and qRT-PCR in EC tissues. KEY FINDINGS: 2573 upregulated and 1890 downregulated genes were identified. A total of 35 genes in the turquoise module were identified as key genes. With multivariate analysis, six genes (DEPDC1, FAM83D, NCAPH, SPC25, TPX2, and TTK) up-regulated in endometrial carcinoma were identified, and their higher expression was associated with a higher stage/age/grade. Moreover, ROC and Kaplan-Meier plots indicated these genes had a high prognostic value for EC. A nomogram was constructed for clinical use. In addition, we explored the pathogenesis involving six genes. The results showed that these genes may become pathogenic as their copy numbers changes and methylation level reduces. Finally, GSEA revealed these genes had a close association with cell cycle, etc. SIGNIFICANCE: These findings may provide new insights into the treatment of diseases.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , RNA Mensageiro/genética , Bases de Dados Genéticas , Neoplasias do Endométrio/patologia , Feminino , Humanos , Células-Tronco Neoplásicas/patologia , Prognóstico
10.
PLoS One ; 15(7): e0235613, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32634176

RESUMO

Germline variants inactivating the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome that implies an increased cancer risk, where colon and endometrial cancer are the most frequent. Identification of these pathogenic variants is important to identify endometrial cancer patients with inherited increased risk of new cancers, in order to offer them lifesaving surveillance. However, several other genes are also part of the MMR pathway. It is therefore relevant to search for variants in additional genes that may be associated with cancer risk by including all known genes involved in the MMR pathway. Next-generation sequencing was used to screen 22 genes involved in the MMR pathway in constitutional DNA extracted from full blood from 199 unselected endometrial cancer patients. Bioinformatic pipelines were developed for identification and functional annotation of variants, using several different software tools and custom programs. This facilitated identification of 22 exonic, 4 UTR and 9 intronic variants that could be classified according to pathogenicity. This study has identified several germline variants in genes of the MMR pathway that potentially may be associated with an increased risk for cancer, in particular endometrial cancer, and therefore are relevant for further investigation. We have also developed bioinformatics strategies to analyse targeted sequencing data, including low quality data and genomic regions outside of the protein coding exons of the relevant genes.


Assuntos
Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/patologia , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Variações do Número de Cópias de DNA , DNA de Neoplasias/sangue , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , Neoplasias do Endométrio/genética , Éxons , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons , Fatores de Risco , Regiões não Traduzidas/genética
11.
Am J Surg Pathol ; 44(8): 1104-1111, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32604171

RESUMO

Mixed endometrial carcinomas are defined as a combination of 2 or more distinct histologic subtypes, one of which must be a type II tumor comprising at least 5% of the tumor volume. The oncogenesis of these tumors remains unclear, particularly in light of the increasingly appreciated morphologic overlap among subtypes, as well as evolving molecular data. We evaluated 8 cases of mixed endometrial carcinoma, including 4 endometrioid (EC)/serous (SC), 1 SC/clear cell (CC), and 3 EC/CC cases, to study the underlying molecular features and oncogenic mechanisms at play. Each component was analyzed by a targeted next-generation sequencing assay. All tumors shared mutations in both components. In 6 cases, one component showed additional mutations. Two EC/SC cases showed shared mutations and mutations unique to each component. When present, unique mutations were typically seen in the SC component, including variants in POLE and TP53, as well as potentially targetable genes DDR2, MAP2K1, and CCNE1. In EC/SC tumors, ERBB2 abnormalities were seen in 2 cases. EC/CC cases showed FGFR2 activating mutations in the EC component only. No fusion drivers were identified. Our data suggest that the majority of these tumors begin as a single clone and diverge along 2 pathways: (1) tumor progression, with one component showing additional mutations, and (2) tumor divergence, in which tumor components have both shared mutations and mutations unique to each component. In addition, the findings suggest a component of morphologic mimicry in these tumors. Our findings are clinically relevant since targetable mutations may be present in only one component of mixed tumors.


Assuntos
Adenocarcinoma de Células Claras/genética , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Mutação , Neoplasias Complexas Mistas/genética , Neoplasias Císticas, Mucinosas e Serosas/genética , Adenocarcinoma de Células Claras/química , Adenocarcinoma de Células Claras/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carcinoma Endometrioide/química , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/química , Neoplasias do Endométrio/patologia , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Neoplasias Complexas Mistas/química , Neoplasias Complexas Mistas/patologia , Neoplasias Císticas, Mucinosas e Serosas/química , Neoplasias Císticas, Mucinosas e Serosas/patologia , Fenótipo
12.
Anticancer Res ; 40(7): 3811-3818, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620620

RESUMO

BACKGROUND/AIM: The objective of this study was to determine the molecular and clinicopathological features, as well as the prognosis of patients with endometrial cancer (EC) having prior malignancy (second primary EC: SPEC) compared with those without a history of prior malignancy (first primary EC: FPEC). MATERIALS AND METHODS: We enrolled 294 FPEC patients and 32 SPEC patients who had undergone surgical resection with curative intent. EC was divided into four groups according to Cancer Genome Atlas Research Network (TCGA) classification. RESULTS: SPEC patients having greater than a 10-year interval from prior malignancy had risk factors including type II histology, deeper myometrial invasion, cervical invasion, and copy number high (CNH) phenotype compared with patients having less than a 10-year interval (p=0.007, p=0.002, p=0.015 and p=0.001). CONCLUSION: SPEC patients having greater than a 10-year interval from prior malignancy possessed numerous high-risk factors for EC.


Assuntos
Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/patologia , Idoso , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/cirurgia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Imuno-Histoquímica , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/cirurgia , Prognóstico
13.
PLoS One ; 15(7): e0236402, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32701999

RESUMO

BACKGROUND: Endometrial cancer (EC) mortality is particularly high among non-Hispanic Blacks and is twice that of non-Hispanic Whites. However, comparisons of EC survival outcomes by race/ethnicity are often confounded by histology and grade. Here, we analyze EC survival disparities in multiracial Florida with a focus on EC types (1 and 2) and subtypes, defined according to histology and grade. METHODS: All 27,809 cases of EC diagnosed during 2005-2016 were obtained from the Florida Cancer Registry. Age-standardized, 5-year cause-specific survival by race/ethnicity and histological type were calculated. Fine and Gray competing risk regression was used to estimate sub-distribution hazard ratios (sHRs) for associations between risk of death due to EC and potential predictive factors such as histology/grade, age, stage at diagnosis, and insurance. RESULTS: Type 2 EC accounted for only 38.7% of all incident EC-cases but 74.6% of all EC-deaths. Blacks were disproportionately affected by type 2 EC (57.6%) compared to Whites, Hispanics, and Asians (35.6%, 37.7%, and 43.0%, respectively). Age-adjusted 5-year survival for types 1 and 2 were 85.3% and 51.6%, respectively; however, there was wide variation within type 2 subtypes, ranging from 60.2% for mixed cell EC to as low as 30.1% for carcinosarcoma. In the multivariable model, Blacks with type 2 EC had a 23% higher risk of death due to EC (sHR: 1.23, 95%CI: 1.12-1.36) compared to Whites. CONCLUSIONS: Population-based analyses should consider the histological heterogeneity of EC because the less common type 2 EC drives racial/ethnic survival disparities in EC. Black women have a higher proportion of more aggressive histological types and an overall higher risk of death due to EC than Whites. To the extent that some of these histological types may be considered different diseases and require specific treatment approaches, further research on etiology and prognosis for detailed type 2 EC subtypes is warranted.


Assuntos
Sobreviventes de Câncer , Neoplasias do Endométrio/epidemiologia , Endométrio/patologia , Neoplasias Uterinas/epidemiologia , Adolescente , Adulto , Afro-Americanos/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Intervalo Livre de Doença , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Florida/epidemiologia , Disparidades nos Níveis de Saúde , Hispano-Americanos/genética , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Adulto Jovem
14.
PLoS One ; 15(6): e0233900, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520976

RESUMO

OBJECTIVES: To identify differences in the mutational profile of endometrial tumours between British White (BW) and South Asian (BSA) women. METHODS: We analysed primary tumours from matched cohorts of British White (BW) and British South Asian (BSA) women resident in Leicestershire diagnosed with EC. Next Generation Sequencing was performed to investigate mutational differences in a panel of 10 genes previously identified as being commonly mutated in EC. The presence of somatic Mismatch Repair (MMR) gene deficiencies was determined by immunohistochemistry. RESULTS: In total, 57 tumours (27 BSA and 30 BW) were sequenced. There was no significant difference in the overall mutation frequency of the 10 genes analysed; however, numerous differences were observed between the groups. There was a positive association between PIK3CA and PTEN mutations in the BSA group, with 78% of PIK3CA-mutant tumours harbouring a PTEN mutation, whereas only 11% of PIK3CA wild-type (wt) tumours were PTEN mutant positive (p = 0.0012). In BW women, 90% of ARID1A mutant tumours had co-existent PI3K pathway mutations versus 50% of wild-type (wt) ARID1A patients (p = 0.0485). This trend was not significant in the BSA group (p = 0.66). The age at diagnosis was significantly higher in the BW group with a somatic MMR gene deficiency compared to those with no deficiency (72.8 years versus 59.6 years, p = 0.007), whereas this difference was not seen in the BSA group (64 years versus 60 years, p = 0.37). CONCLUSION: We have identified differences in the mutational profile of primary EC tumours from BW and BSA women. Further research is needed to confirm these findings and to explore their potential implications for early detection, treatment response and prognosis.


Assuntos
Carcinoma Endometrioide/genética , Enzimas Reparadoras do DNA/genética , DNA de Neoplasias/genética , Neoplasias do Endométrio/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Estudos de Coortes , Análise Mutacional de DNA/métodos , Grupo com Ancestrais do Continente Europeu , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pessoa de Meia-Idade , Mutação , Reino Unido
15.
Medicine (Baltimore) ; 99(25): e20793, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569224

RESUMO

OBJECTIVE: To study the relationship between single nucleotide polymorphism (SNP) of the 3 primer untranslated region (UTR) variants of the cell fate determination factor Dachshund 1(DACH1) gene and the susceptibility of patients with endometrial cancer (EC). METHODS: Genomic DNA was extracted from the peripheral venous blood of 235 EC patients and 235 healthy controls, and the DACH1 gene rs9285274, rs9529895, rs17088351, and rs59352399 loci were analyzed by Sanger sequencing. Patients progression-free survival (PFS) was recorded after 3 years follow-up from October 2016 to October 2019. RESULTS: Carriers of the C allele of the DACH1 gene rs9529895 locus had a significantly lower risk for EC than T allele carriers (odds ratio = 0.56, 95%confidence interval: 0.38-0.84, P < .01). The correlation between DACH1 gene rs9529895 locus SNP and the risk for EC was affected by age, body mass index, smoking, drinking, and diabetes. Age, and rs9285274, rs9529895, and rs59352399 locus SNP were the best models for predicting the risk for EC. The accuracy rate was 57.02%, and the Cross-validation Consistency was 10/10 (x = 4.33, P = .04). The DACH1 gene rs9529895 locus C allele (TC+CC) carriers had significantly higher PFS than the TT genotype carriers (P = .04). The DACH1 gene was expressed in decreased amounts in the cancer tissues of EC patients, and the DACH1 mRNA expression level in the CC genotype, TC genotype, and TT genotype of rs9529895 locus was also decreased (P = .02). CONCLUSION: DACH1 gene rs9529895 locus SNP is significantly related to the risk for EC and PFS of EC patients. The possible mechanism behind this relationship is that the DACH1 gene rs9529895 locus SNP affects DACH1 expression level.


Assuntos
Neoplasias do Endométrio/genética , Proteínas do Olho/genética , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Regiões 3' não Traduzidas/genética , Sítios de Ligação/genética , Western Blotting , Estudos de Casos e Controles , Proteínas do Olho/metabolismo , Feminino , Predisposição Genética para Doença/genética , Humanos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/metabolismo
16.
Nat Commun ; 11(1): 2717, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483112

RESUMO

Somatic inactivating mutations of ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human endometrium-related malignancies. To elucidate the mechanisms underlying how ARID1A deleterious mutation contributes to tumorigenesis, we establish genetically engineered murine models with Arid1a and/or Pten conditional deletion in the endometrium. Transcriptomic analyses on endometrial cancers and precursors derived from these mouse models show a close resemblance to human uterine endometrioid carcinomas. We identify transcriptional networks that are controlled by Arid1a and have an impact on endometrial tumor development. To verify findings from the murine models, we analyze ARID1AWT and ARID1AKO human endometrial epithelial cells. Using a system biology approach and functional studies, we demonstrate that ARID1A-deficiency lead to loss of TGF-ß tumor suppressive function and that inactivation of ARID1A/TGF-ß axis promotes migration and invasion of PTEN-deleted endometrial tumor cells. These findings provide molecular insights into how ARID1A inactivation accelerates endometrial tumor progression and dissemination, the major causes of cancer mortality.


Assuntos
Carcinogênese/genética , Carcinoma Endometrioide/genética , Reprogramação Celular/genética , Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/genética , Fatores de Transcrição/genética , Animais , Carcinogênese/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Endométrio/citologia , Endométrio/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Mutação , Fatores de Transcrição/metabolismo
17.
DNA Cell Biol ; 39(5): 875-889, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32354230

RESUMO

Several studies have revealed that miR-205 plays important roles in the development of gynecological cancers and thus may serve as a potential prognostic biomarker, but the current conclusions remain controversial. Therefore, the goal of this study was to explore the prognostic significance and functional mechanisms of miR-205 based on a meta-analysis and bioinformatics investigation. A total of 14 published studies containing 5835 patients were enrolled by searching the PubMed, EMBASE, and Cochrane library databases, 13 (14 datasets) and 5 (6 datasets) of which evaluated the correlations between the expression level of miR-205 and overall survival (OS) or disease-free survival (DFS)/disease-specific survival (DSS)/progression-free survival (PFS)/distant metastasis-free survival (DMFS), respectively. Furthermore, the use of online Kaplan-Meier plotter database analysis supplemented another seven results for OS. Then, a meta-analysis using these 21 and 6 datasets was performed. As a result, the overall analysis failed to demonstrate any significant associations between miR-205 expression and OS (p = 0.267) or DSS/DFS/DMFS/PFS (p = 0.457), but the subgroup analysis suggested that elevated miR-205 predicted a reduced OS for breast cancer (BC) patients (hazard ratio [HR] = 0.84, 95% confidence interval [CI] = 0.72-0.98; p = 0.022), while higher miR-205 was associated with a poor DSS for endometrial cancer (EC) patients (HR = 2.19, 95% CI = 1.45-3.32; p < 0.001). Function prediction analysis indicated that miR-205 may be involved in BC by negatively influencing hub genes, SMARCA5 and SIAH1, whereas miR-205 may participate in EC by negatively modulating BMPR1B because of the presence of interactions of miR-205 with them at 3'-untranslated region and their opposite prognosis outcomes with miR-205. In conclusion, our findings suggest miR-205 may be a promising prognostic biomarker and therapeutic target for BC and EC patients.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , MicroRNAs/genética , Neoplasias da Mama/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Prognóstico
18.
Nature ; 580(7805): 640-646, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32350471

RESUMO

All normal somatic cells are thought to acquire mutations, but understanding of the rates, patterns, causes and consequences of somatic mutations in normal cells is limited. The uterine endometrium adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium1,2. Here, using whole-genome sequencing, we show that normal human endometrial glands are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers. Normal endometrial glands frequently carry 'driver' mutations in cancer genes, the burden of which increases with age and decreases with parity. Cell clones with drivers often originate during the first decades of life and subsequently progressively colonize the epithelial lining of the endometrium. Our results show that mutational landscapes differ markedly between normal tissues-perhaps shaped by differences in their structure and physiology-and indicate that the procession of neoplastic change that leads to endometrial cancer is initiated early in life.


Assuntos
Análise Mutacional de DNA , Endométrio/citologia , Endométrio/metabolismo , Epitélio/metabolismo , Saúde , Mutação , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Carcinogênese/genética , Células Clonais/citologia , Neoplasias do Endométrio/genética , Endométrio/patologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Epitélio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Paridade/genética , Fatores de Tempo , Adulto Jovem
19.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(1): 20-26, 2020 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-32376564

RESUMO

OBJECTIVE: To investigate the effect of overexpression of leukemia inhibitory factor (LIF) on cisplatin and paclitaxel resistance of endometrial cancer cells in vitro. METHODS: Endometrial cancer cell lines HEC-1B and RL95-2 were infected with a recombinant lentivirus to overexpress LIF, and the changes in LIF expression was verified using RT-qPCR and ELISA. The viability of the LIF-overexpressing cells was assessed using CCK-8 assay, and the cell apoptosis and changes in mitochondrial membrane potential in response to cisplatin or paclitaxel treatment were analyzed with annexin V-FITC/PI staining and JC-1 assay, respectively. The effect of LIF overexpression on the expressions of Bcl-2 family proteins and STAT3 pathway was evaluated using Western blotting; dual-luciferase reporter gene assay was employed to detect the transcriptional activity of STAT3. The effect of STAT3 silencing on apoptosis of the LIF-overexpressing cells induced by cisplatin or paclitaxel was investigated. RESULTS: The cell lines infected with the recombinant lentivirus showed significantly increased mRNA and protein levels of LIF (P < 0.05) without obvious changes in the cell viability (P>0.05). LIF overexpression significantly attenuated cisplatin-or paclitaxel-induced apoptosis of the endometrial cancer cells (P < 0.05) and markedly increased mitochondrial membrane potential of the cells (P < 0.05). The expressions of Bcl-2, Bcl-xL and p-STAT3 proteins increased obviously while the expressions of Bax, Bad and STAT3 either decreased or showed no obvious changes in the LIF-overexpressing cells. Overexpressing LIF significantly enhanced the transcriptional activity of STAT3 (P < 0.05), and silencing STAT3 obviously enhanced apoptosis of the endometrial cancer cells overexpressing LIF (P < 0.05). CONCLUSIONS: s Overexpression of LIF can enhance cisplatin and paclitaxel resistance to endometrial cancer cells in vitro.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias do Endométrio/genética , Fator Inibidor de Leucemia/genética , Paclitaxel/farmacologia , Transdução de Sinais , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Feminino , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína bcl-X/metabolismo
20.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(1): 61-66, 2020 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-32376567

RESUMO

OBJECTIVE: To investigate the role of microRNA-145-5p (miR-145-5p) in regulating the proliferation, migration, invasion and apoptosis of human endometrial carcinoma cells. METHODS: Human endometrial carcinoma Ishikawa cells were transfected with miR-145-5p mimic, miR-145-5p inhibitor, or their negative controls via liposome (Lipo2000), and the changes in the expression of miR-145-5p was verified by real-time PCR. The effects of overexpression or inhibition of miR-145-5p on the proliferation, migration, invasion and apoptosis of the cells were evaluated using MTT assay, wound healing assay, Transwell assay or flow cytometry. Bioinformatic analysis was performed to predict the target genes of miR-145-5p. The mRNA and protein expression levels of the downstream target of miR-145-5p, namely dual specific phosphatase 6 (DUSP6), were detected using real-time PCR and Western blotting. RESULTS: Transfection of the cells with miR-145-5p mimic significantly suppressed the proliferation of Ishikawa cells, while transfection with miR-145-5p inhibitor obvious enhanced the proliferation of the cells (P < 0.05). Over-expression of miR-145-5p significantly suppressed the migration and invasion and promoted apoptosis of the cells, and inhibition of miR-145-5p caused the reverse changes (P < 0.05). Bioinformatic analysis showed that DUSP6 was the potential target gene of miR-145-5p. Over-expression of miR-145-5p significantly lowered while inhibition of miR-145-5p significantly enhanced the expression of DUSP6 protein (P < 0.05). CONCLUSIONS: Overexpression of miR-145-5p inhibits the proliferation, migration and invasion and promotes apoptosis of endometrial cancer cells possibly by negative regulation of DUSP6 expression.


Assuntos
Fosfatase 6 de Especificidade Dupla/genética , Neoplasias do Endométrio/patologia , MicroRNAs/genética , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias do Endométrio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...