Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.558
Filtrar
1.
Anticancer Res ; 40(11): 6017-6028, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109540

RESUMO

BACKGROUND/AIM: R-spondins control WNT signaling and RSPO1 and LGR6, two of its receptors, are uniquely expressed at high levels in high-grade serous ovarian cancer (HGSOC). The aim of this study was to assess the interrelations between the expression of the RSPOs and LGRs in HGSOC and in the ovarian surface (OSE) and fallopian tube surface epithelium (FTSE) from which HGSOC arises. MATERIALS AND METHODS: Analysis of TCGA (HGSOC), CCLE (ovary), and other publicly accessed RNA-Seq data using UC San Diego Computational Cancer Analysis Library (CCAL) to perform differential expression analysis, association studies, and gene set inspection using the single-sample GSEA method. Additionally, we employed multiple publicly available databases including StringDB, Human Protein Atlas, and cBioPortal to aid the investigation. RESULTS: Among normal tissues, expression of RSPO1, LGR5 and LGR6 was highest in the fallopian tube. The relative levels of expression of the RSPOs and LGRs in the OSE and FTSE matched those in HGSOC. RSPO1 and LGR6 were highly co-expressed in all three tissues. Gene set enrichment analysis (GSEA) showed that expression of RSPO1 was strongly linked to the enrichment of three separate WNT-driven GO pathways. Analysis of genes that impacted overall survival identified two other immediately adjacent genes that control WNT signaling, KREMEN1 and ZNRF3 whose expression and copy number were coordinately linked. CONCLUSION: RSPO1 and LGR6 are coordinately expressed in HGSOC and the two normal tissues from which this tumor arises, and their expression is linked to WNT signaling pathways known the control cell fate and proliferation.


Assuntos
Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptores Acoplados a Proteínas-G/metabolismo , Trombospondinas/metabolismo , Via de Sinalização Wnt , Cistadenocarcinoma Seroso/genética , Tubas Uterinas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Gradação de Tumores , Neoplasias Ovarianas/genética , Ovário/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas-G/genética , Trombospondinas/genética , Via de Sinalização Wnt/genética
2.
Am J Hum Genet ; 107(4): 622-635, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32946763

RESUMO

Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this study we first estimated the heritability explained by known common low penetrance risk alleles for EOC. The narrow sense heritability (hg2) of EOC overall and high-grade serous ovarian cancer (HGSOCs) were estimated to be 5%-6%. Partitioned SNP heritability across broad functional categories indicated a significant contribution of regulatory elements to EOC heritability. We collated epigenomic profiling data for 77 cell and tissue types from Roadmap Epigenomics and ENCODE, and from H3K27Ac ChIP-seq data generated in 26 ovarian cancer and precursor-related cell and tissue types. We identified significant enrichment of risk single-nucleotide polymorphisms (SNPs) in active regulatory elements marked by H3K27Ac in HGSOCs. To further investigate how risk SNPs in active regulatory elements influence predisposition to ovarian cancer, we used motifbreakR to predict the disruption of transcription factor binding sites. We identified 469 candidate causal risk variants in H3K27Ac peaks that are predicted to significantly break transcription factor (TF) motifs. The most frequently broken motif was REST (p value = 0.0028), which has been reported as both a tumor suppressor and an oncogene. Overall, these systematic functional annotations with epigenomic data improve interpretation of EOC risk variants and shed light on likely cells of origin.


Assuntos
Carcinoma Epitelial do Ovário/genética , Proteínas Correpressoras/genética , Cistadenocarcinoma Seroso/genética , Elementos Facilitadores Genéticos , Histonas/genética , Proteínas do Tecido Nervoso/genética , Neoplasias Ovarianas/genética , Alelos , Sítios de Ligação , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/patologia , Mapeamento Cromossômico , Proteínas Correpressoras/metabolismo , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/patologia , Feminino , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Padrões de Herança , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Penetrância , Polimorfismo de Nucleotídeo Único , Risco
3.
Am J Pathol ; 190(11): 2304-2316, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32805233

RESUMO

S100A4 is a small calcium-binding protein that exerts its biological functions by interacting with nonmuscle myosin IIA (NMIIA) and p53. Although S100A4 promotes metastasis in several tumors, little is known about its involvement in the progression of ovarian high-grade serous carcinomas (HGSCs). Herein, we focused on functional roles of the S100A4/NMIIA/p53 axis in these tumors. In HGSC cell lines harboring mutant p53, knockdown (KD) of S100A4 reduced the expression of several epithelial-mesenchymal transition/cancer stem cell markers and the ALDH1high population, consistent with an inhibition of stemness features. S100A4-KD also increased apoptosis, decreased cell proliferation, and accelerated cell mobility. This was accompanied by increased Snail expression, which, in turn, was likely due to loss of p53 function. In contrast, specific inhibition of NMIIA by blebbistatin induced phenotypes that-with the exception of cell proliferation and mobility-were opposite to those observed in S100A4-KD cells. In clinical samples, cytoplasmic and/or nuclear interactions between S100A4, NMIIA, and mutant p53 were observed. In addition, high expression of S100A4, but not NMIIA or p53, was a significant and independent unfavorable prognostic factor in HGSC patients. These findings suggest that, via its interaction with NMIIA and p53, overexpressed S100A4 may induce epithelial-mesenchymal transition/cancer stem cell properties in HGSC and elicit several other tumor-associated phenotypes.


Assuntos
Cistadenocarcinoma Seroso/metabolismo , Células-Tronco Neoplásicas/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Neoplasias Ovarianas/metabolismo , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Cistadenocarcinoma Seroso/patologia , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/patologia , Fatores de Transcrição da Família Snail/biossíntese
4.
PLoS One ; 15(7): e0235766, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32639993

RESUMO

High-grade serous ovarian carcinoma (HGSOC) remains the deadliest form of epithelial ovarian cancer and despite major efforts little improvement in overall survival has been achieved. Identification of recurring "driver" genetic lesions has the potential to enable design of novel therapies for cancer. Here, we report on a study to find such new therapeutic targets for HGSOC using exome-capture sequencing approach targeting all kinase genes in 127 patient samples. Consistent with previous reports, the most frequently mutated gene was TP53 (97% mutation frequency) followed by BRCA1 (10% mutation frequency). The average mutation frequency of the kinase genes mutated from our panel was 1.5%. Intriguingly, after BRCA1, JAK3 was the most frequently mutated gene (4% mutation frequency). We tested the transforming properties of JAK3 mutants using the Ba/F3 cell-based in vitro functional assay and identified a novel gain-of-function mutation in the kinase domain of JAK3 (p.T1022I). Importantly, p.T1022I JAK3 mutants displayed higher sensitivity to the JAK3-selective inhibitor Tofacitinib compared to controls. For independent validation, we re-sequenced the entire JAK3 coding sequence using tagged amplicon sequencing (TAm-Seq) in 463 HGSOCs resulting in an overall somatic mutation frequency of 1%. TAm-Seq screening of CDK12 in the same population revealed a 7% mutation frequency. Our data confirms that the frequency of mutations in kinase genes in HGSOC is low and provides accurate estimates for the frequency of JAK3 and CDK12 mutations in a large well characterized cohort. Although p.T1022I JAK3 mutations are rare, our functional validation shows that if detected they should be considered as potentially actionable for therapy. The observation of CDK12 mutations in 7% of HGSOC cases provides a strong rationale for routine somatic testing, although more functional and clinical characterization is required to understand which nonsynonymous mutations alterations are associated with homologous recombination deficiency.


Assuntos
Proteína BRCA1/genética , Cistadenocarcinoma Seroso/genética , Janus Quinase 3/genética , Mutação , Neoplasias Ovarianas/genética , Proteínas Quinases/genética , Proteína Supressora de Tumor p53/genética , Proteína BRCA1/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Janus Quinase 3/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Quinases/metabolismo , Proteína Supressora de Tumor p53/metabolismo
5.
J Surg Oncol ; 122(2): 315-319, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32500598

RESUMO

BACKGROUND: The aim of our study was to investigate whether metastatic patterns were associated with the prognosis of patients with FIGO stage IV high-grade serous ovarian cancer (HGSC). METHODS: We retrospectively investigated 83 consecutive patients with FIGO stage IV HGSC who underwent primary surgery between April 2005 and June 2013 at our institution. Metastatic patterns were defined as pleural effusion (stage IVA), parenchymal metastases (stage IVB), and extra-abdominal lymph node metastases (stage IVB). Correlations of clinical characteristics and prognosis with metastatic patterns were analyzed. RESULTS: Forty-two (50.6%) patients were stage IVA with pleural effusion. Among the remaining stage IVB patients, 19 (22.9%) patients had parenchymal metastases and 22 (26.5%) had extra-abdominal lymph node metastases. FIGO IVA and IVB subclassification did not have a prognostic impact on progression-free survival (PFS) (P = .361). In addition, no differences in PFS were observed among patients presenting the three metastatic patterns (P = .506). The 5-year overall survival (OS) rates of patients with stage IVA and IVB diseases were 35.2% and 34.3%, respectively, (P = .856). In addition, metastatic patterns did not provide additional prognostic information for OS (P = .292). CONCLUSION: Neither the subclassification into FIGO IVA and IVB stages nor metastatic patterns of FIGO stage IV provided additional prognostic information.


Assuntos
Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/cirurgia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Derrame Pleural Maligno/patologia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento
6.
Lancet Oncol ; 21(7): 957-968, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32553118

RESUMO

BACKGROUND: High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer. METHODS: In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Eligible patients were randomly assigned (1:1) to receive intravenous gemcitabine (1000 mg/m2) on day 1 and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m2) on day 2 and day 9 of a 21-day cycle until disease progression or intolerable toxicity. Randomisation was done centrally using the Theradex Interactive Web Response System, stratified by platinum-free interval, and with a permuted block size of six. Following central randomisation, patients and investigators were not masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival, and analyses included all patients who received at least one dose of the study drugs. The study is registered with ClinicalTrials.gov, NCT02595892, and is active but closed to enrolment. FINDINGS: Between Feb 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, of whom 70 were randomly assigned to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). At the data cutoff date (Feb 21, 2020), the median follow-up was 53·2 weeks (25·6-81·8) in the gemcitabine plus berzosertib group and 43·0 weeks (IQR 23·2-69·1) in the gemcitabine alone group. Median progression-free survival was 22·9 weeks (17·9-72·0) for gemcitabine plus berzosertib and 14·7 weeks (90% CI 9·7-36·7) for gemcitabine alone (hazard ratio 0·57, 90% CI 0·33-0·98; one-sided log-rank test p=0·044). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (14 [39%] of 36 patients in the gemcitabine alone group vs 16 [47%] of 34 patients in the gemcitabine plus berzosertib group) and decreased platelet count (two [6%] vs eight [24%]). Serious adverse events were observed in ten (28%) patients in the gemcitabine alone group and nine (26%) patients in the gemcitabine plus berzosertib group. There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the gemcitabine plus berzosertib group due to pneumonitis. INTERPRETATION: To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting. FUNDING: US National Cancer Institute.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cistadenocarcinoma Seroso/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Terapia de Salvação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cistadenocarcinoma Seroso/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Seguimentos , Humanos , Isoxazóis/administração & dosagem , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/patologia , Platina/farmacologia , Pirazinas/administração & dosagem , Taxa de Sobrevida , Adulto Jovem
8.
Sci Rep ; 10(1): 6688, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317693

RESUMO

Peritoneal spread indicates poor prognosis in patients with serous ovarian carcinoma (SOC) and is generally treated by surgical cytoreduction and chemotherapy. Novel treatment options are urgently needed to improve patient outcome. Clinically relevant cell lines and patient-derived xenograft (PDX) models are of critical importance to therapeutic regimen evaluation. Here, a PDX model was established, by orthotopic engraftment after subperitoneal tumor slurry injection of low-grade SOC, resulting in an early-stage transplantable peritoneal metastasis (PM)-PDX model. Histology confirmed the micropapillary and cribriform growth pattern with intraluminal tumor budding and positivity for PAX8 and WT1. PM-PDX dissociated cells show an epithelial morphotype with a 42 h doubling time and 40% colony forming efficiency, they are low sensitive to platinum derivatives and highly sensitive to paclitaxel (IC50: 6.3 ± 2.2 nM, mean ± SEM). The patient primary tumor, PM, PM-PDX and derived cell line all show a KRAS c.35 G > T (p.(Gly12Val)) mutation and show sensitivity to the MEK inhibitor trametinib in vitro (IC50: 7.2 ± 0.5 nM, mean ± SEM) and in the PM mouse model. These preclinical models closely reflecting patient tumors are useful to further elucidate LGSOC disease progression, therapy response and resistance mechanisms.


Assuntos
Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Feminino , Humanos , Camundongos SCID , Repetições de Microssatélites/genética , Mutação/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico
9.
Nat Commun ; 11(1): 1640, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242007

RESUMO

High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.


Assuntos
Cistadenocarcinoma Seroso/genética , Exoma , Heterogeneidade Genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Mutação com Perda de Função , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
10.
Artigo em Inglês | MEDLINE | ID: mdl-32316405

RESUMO

The role of microRNA (miRNA) in ovarian cancer has been extensively studied as a regulator for its targeted genes. However, its specific role in metastatic serous ovarian cancer (SOC) is yet to be explored. This paper aims to investigate the differentially expressed miRNAs in metastatic SOC compared to normal. Locked nucleic acid PCR was performed to profile miRNA expression in 11 snap frozen metastatic SOC and 13 normal ovarian tissues. Functional analysis and regulation of their targeted genes were assessed in vitro. Forty-eight miRNAs were significantly differentially expressed in metastatic SOC as compared to normal. MiR-19a is a novel miRNA to be upregulated in metastatic SOC compared to normal. DLC1 is possibly regulated by miR-141 in SOC. MiR-141 inhibition led to significantly reduced cell viability. Cell migration and invasion were significantly increased following miRNA inhibition. This study showed the aberrantly expressed miRNAs in metastatic SOC and the roles of miRNAs in the regulation of their targeted genes and ovarian carcinogenesis.


Assuntos
Carcinoma Epitelial do Ovário , Cistadenocarcinoma Seroso , Proteínas Ativadoras de GTPase , MicroRNAs , Neoplasias Ovarianas , Proteínas Supressoras de Tumor , Homeobox 2 de Ligação a E-box com Dedos de Zinco , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Movimento Celular , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Proteínas Ativadoras de GTPase/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Supressoras de Tumor/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo
11.
Rev Mal Respir ; 37(4): 341-345, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32284205

RESUMO

In systemic sclerosis, the presence of an anti-RNA polymerase III antibody (ARNpol3) is associated with an increased risk of cancer. The characteristic picture of this serotype includes severe diffuse cutaneous involvement, a high risk of renal scleroderma crisis and a 10 year survival of only around 30%. Pulmonary involvement is less common. We report the case of a woman initially treated for drug-induced acute interstitial lung disease revealing chronic interstitial pneumonia with autoimmune features. The disease evolved in three stages with the occurrence of a rapidly progressive diffuse skin sclerosis with anti-ARNPol3 antibodies in the context of ovarian cancer remission.


Assuntos
Cistadenocarcinoma Seroso/complicações , Flecainida/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Neoplasias Ovarianas/complicações , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Idoso , Autoanticorpos/sangue , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/terapia , Feminino , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , RNA Polimerase III/imunologia , Indução de Remissão , Escleroderma Sistêmico/sangue
12.
Bull Cancer ; 107(3): 385-390, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32115180

RESUMO

The group of rare malignant ovarian tumors includes the group of germ cell tumors, sex cords stromal ovarian tumors, small cell carcinoma, malignant Brenner tumors, rare epithelial tumors such as mucinous carcinoma, clear cell carcinoma, or low-grade serous carcinoma, as well as ovarian carcinosarcoma. Together they comprise about 10% of all ovarian tumors. Due to their low prevalence and their heterogeneity, data and treatment recommendations are limited. Even though all ovarian tumors are staged according to the FIGO staging of epithelial ovarian tumors, treatment differs especially in germ cell tumors and sex cords stromal ovarian tumors. Non-epithelial ovarian tumors can arise from a variety of ovarian precursor cells such as germ cells, granulosa cells, theca cells, or stromal fibroblasts. As can be expected already due to their divergent precursor lesions, these malignancies are substantially different but united by their rarity. This overview article gives a comprehensive summary on the pathology and clinical presentation, as well as therapy recommendations of a selection of those rare ovarian tumors, based on the latest national guidelines and related important publications.


Assuntos
Neoplasias Ovarianas , Doenças Raras , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/terapia , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/terapia , Tumor de Brenner/patologia , Tumor de Brenner/terapia , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/terapia , Carcinossarcoma/patologia , Carcinossarcoma/terapia , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/terapia , Feminino , Humanos , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Doenças Raras/patologia , Doenças Raras/terapia , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/terapia
13.
Gynecol Oncol ; 157(2): 555-557, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32192733

RESUMO

OBJECTIVE: Metastatic lymph node resection around the porta hepatis is sometimes required to achieve complete cytoreduction for ovarian, fallopian tube, and primary peritoneal cancer. Hence, this study aimed to present the surgical approach of peripancreatic lymph node removal around the porta hepatis as part of primary debulking surgery. METHODS: A 75-year old woman with stage IIIC primary peritoneal serous carcinoma underwent primary debulking surgery by means of the following procedures: bilateral salpingo-oophorectomy, total hysterectomy, omentectomy, total pelvic peritonectomy, rectosigmoid colectomy with anastomosis, right hemicolectomy, right diaphragm resection, partial jejunal resection, and pelvic and para-aortic lymphadenectomy. Furthermore, she underwent enlarged peripancreatic lymph nodes resection located in the hepatoduodenal ligament and on the posterior pancreatic head. An anatomic variant of the common hepatic artery was identified to be arising from the superior mesenteric artery and not from the celiac artery. The common hepatic artery ran behind the portal vein. We resected the lymph nodes without causing injury of the hepatic artery, portal vein, and common bile duct and achieved complete cytoreduction. RESULTS: The histological examination revealed high-grade serous carcinoma in three of nine resected peripancreatic lymph nodes. In contrast, only one lymph node metastasized in the interaortocaval region among the 63 resected regional lymph nodes (paraaortic and pelvic lymph nodes). CONCLUSION: Metastatic peripancreatic lymph nodes resection around the porta hepatis is feasible and sometimes necessary for cytoreductive surgery for advanced ovarian, fallopian tube, and primary peritoneal cancer.


Assuntos
Cistadenocarcinoma Seroso/cirurgia , Linfonodos/cirurgia , Neoplasias Peritoneais/cirurgia , Idoso , Cistadenocarcinoma Seroso/patologia , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Excisão de Linfonodo , Linfonodos/patologia , Metástase Linfática , Neoplasias Peritoneais/patologia
14.
BMC Cancer ; 20(1): 204, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164585

RESUMO

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors targeting BRCA1/2 mutations are available for treating patients with high-grade serous ovarian cancer. These treatments may be more appropriately directed to patients who might respond if the tumor tissue is additionally tested by next-generation sequencing with a multi-gene panel and Sanger sequencing of a blood sample. In this study, we compared the results obtained using the next-generation sequencing multi-gene panel to a known germline BRCA1/2 mutational state determined by conventional Sanger sequencing to evaluate the landscape of somatic mutations in high-grade serous ovarian cancer tumors. METHODS: Cancer tissue from 98 patients with high-grade serous ovarian cancer who underwent Sanger sequencing for germline BRCA1/2 analysis were consecutively analyzed for somatic mutations using a next-generation sequencing 170-gene panel. RESULTS: Twenty-four patients (24.5%) showed overall BRCA1/2 mutations. Seven patients (7.1%) contained only somatic BRCA1/2 mutations with wild-type germline BRCA1/2, indicating acquired mutation of BRCA1/2. Three patients (3.1%) showed reversion of germline BRCA1 mutations. Among the 14 patients (14.3%) with both germline and somatic mutations in BRCA1/2, two patients showed different variations of BRCA1/2 mutations. The next-generation sequencing panel test for somatic mutation detected other pathogenic variations including RAD51D and ARID1A, which are possible targets of poly (ADP-ribose) polymerase inhibitors. Compared to conventional Sanger sequencing alone, next-generation sequencing-based tissue analysis increased the number of candidates for poly (ADP-ribose) polymerase inhibitor treatment from 17.3% (17/98) to 26.5% (26/98). CONCLUSIONS: Somatic mutation analysis by next-generation sequencing, in addition to germline BRCA1/2 mutation analysis, should become the standard of care for managing women with high-grade serous ovarian cancer to widen the indication of poly (ADP-ribose) polymerase inhibitors.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Cistadenocarcinoma Seroso/patologia , Proteínas de Ligação a DNA/genética , Mutação , Neoplasias Ovarianas/patologia , Fatores de Transcrição/genética , Adulto , Idoso , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Feminino , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Análise de Sequência de DNA/métodos , Adulto Jovem
15.
BMC Cancer ; 20(1): 197, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164626

RESUMO

BACKGROUND: BRCA1/2 germline mutation related cancers are candidates for new immune therapeutic interventions. This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients. The prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers in this cohort was not correlated with high global immune activity in their microenvironments. More information is needed about the relationship between genomic instability, phenotypes and immune microenvironments of these hereditary tumors in order to find appropriate markers of immune activity and the most effective anticancer immune strategies. METHODS: Mining and statistical analyses of the original DNA and RNA sequencing data and The Cancer Genome Atlas data were performed. To interpret the data, we have used published literature and web available resources such as Gene Ontology, The Cancer immunome Atlas and the Cancer Research Institute iAtlas. RESULTS: We found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but they express a range of phenotypes similar to sporadic cancers. All breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC) also express a high degree of HRD. CONCLUSIONS: TMB is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of "BRCAness" and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition. TRIAL REGISTRATION: Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent TNBC or HGSOC (NCT01623349), first posted on June 20, 2012. The design and the outcome of the clinical trial is not in the scope of this study.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Cistadenocarcinoma Seroso/genética , Perfilação da Expressão Gênica/métodos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Neoplasias Ovarianas/genética , Neoplasias de Mama Triplo Negativas/genética , Cistadenocarcinoma Seroso/patologia , Mineração de Dados , Feminino , Instabilidade Genômica , Mutação em Linhagem Germinativa , Síndrome Hereditária de Câncer de Mama e Ovário/patologia , Recombinação Homóloga , Humanos , Neoplasias Ovarianas/patologia , Análise de Sequência de RNA , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral , Sequenciamento Completo do Genoma
16.
Medicine (Baltimore) ; 99(9): e19383, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32118786

RESUMO

RATIONALE: Breast metastasis from serous borderline tumor with micro-invasive carcinoma of ovary is a very rare condition. The breast lump as the only clinical presentation is rarely seen in ovarian carcinoma, which may lead to be misdiagnosed, and the mechanism of breast metastasis from ovarian tumors in early stage still needs to be explored. Differentiation from primary breast cancer and extramammary malignancy is crucial because the treatment and prognosis are significantly different. PATIENT CONCERNS: A 33-year-old female presented with a painless, movable, 1.0 × 1.0 cm lump in the upper outer quadrant of the right breast for a month. DIAGNOSES: Breast metastasis of serous borderline tumor with micro-invasive ovarian carcinoma confirmed by pathology and immunohistochemistry. INTERVENTIONS: The patient underwent lumpectomy, bilateral ovarian tumor stripping operation and prophylactic chemotherapy. OUTCOMES: No signs of recurrence have been detected in 1.5 years of follow-up. LESSONS: Distant metastasis may occur in early stage of ovarian carcinoma. It is important to determine the origin of the primary tumor and develop an effective treatment strategy for patients. Imaging findings and pathological diagnostic criteria are important to accurately differentiate between metastasis and primary breast lesions, which may improve the patient's outcomes.


Assuntos
Neoplasias da Mama/diagnóstico , Metástase Neoplásica/diagnóstico , Neoplasias Ovarianas/complicações , Adulto , Neoplasias da Mama/etiologia , Neoplasias da Mama/fisiopatologia , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/etiologia , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Metástase Neoplásica/patologia , Neoplasias Ovarianas/fisiopatologia , Ultrassonografia/métodos
17.
Medicina (Kaunas) ; 56(3)2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32138225

RESUMO

Background and objectives: To identify the risk factors for para-aortic lymph node metastases in cases with presumed early stage ovarian cancer. Materials and methods: Between 2014 and 2019, 48 patients with apparent early stage ovarian cancer were submitted to surgery. In all cases, pelvic and para-aortic lymph node dissection was performed for staging purposes. Results: Among the 48 cases we identified nine cases with positive pelvic lymph nodes and 11 cases with positive para-aortic lymph nodes. The positivity of the retrieved lymph nodes was significantly correlated with the histopathological subtype represented by serous histology (p = 0.02), as well as with the degree of differentiation (p = 0.004). Conclusion: Patients with serous ovarian carcinomas in association with a poorer degree of differentiation are at risk of associated lymph node metastases even in presumed early stages of the disease. Therefore, lymph node dissection should be performed in such cases in order to provide adequate staging and tailoring of further treatment.


Assuntos
Cistadenocarcinoma Seroso/patologia , Linfonodos/patologia , Metástase Linfática/diagnóstico , Neoplasias Ovarianas/patologia , Adulto , Aorta , Quimioterapia Adjuvante , Feminino , Humanos , Excisão de Linfonodo , Menopausa , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco
18.
BMC Cancer ; 20(1): 185, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131779

RESUMO

BACKGROUND: To analyze the effects of BRCA1/2 mutations on chemotherapy response scores (CRS) and survival in a cohort of patients with advanced-stage ovarian cancer who were treated with neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS). METHODS: We retrospectively reviewed the medical records of 169 high-grade serous ovarian cancer patients who underwent a germline BRCA1/2 test and received three cycles of NAC at the Yonsei Cancer Center from 2006 to 2018. Chemotherapy response scores were compared in patients with and without BRCA1/2 mutations. The effects of BRCA1/2 mutations and CRS on survival were evaluated. RESULTS: BRCA1/2 mutations were detected in 47 (28.1%) of the 169 patients. Overall, 16 (34.0%) patients with BRCA1/2 mutations had a CRS 3 to chemotherapy compared to scores of 43 in patients (35.2%) without a mutation. Response scores of 3 in patients with BRCA1/2 mutations were not significantly associated with either improved progression-free survival (PFS) (P = 0.949) or overall survival (OS) (P = 0.168). However, CRS 3 in patients without BRCA mutations was significantly associated with both improved PFS (P = 0.030) and OS (P = 0.039). In patients with CRS1/2, carriers of BRCA1/2 mutations had better PFS (P = 0.0344) and OS (P = 0.043) than wild-type BRCA genotype patients. CONCLUSION: In ovarian cancer patients treated with NAC, CRS did not predict survival for BRCA 1/2 mutation carriers but did for BRCA wild-type patients.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Cistadenocarcinoma Seroso/terapia , Tratamento Farmacológico/métodos , Mutação em Linhagem Germinativa , Procedimentos Cirúrgicos em Ginecologia/métodos , Neoplasias Ovarianas/terapia , Adulto , Idoso , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
19.
Gynecol Oncol ; 157(1): 46-54, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32008792

RESUMO

OBJECTIVE: Low-grade serous carcinoma (LGSC) is a rare histotype of ovarian cancer with a unique disease course. Little data exist regarding the influence of sociodemographic factors on diagnosis and outcomes in this disease. Our objective was to evaluate the associations between these factors and the clinical characteristics, treatment approaches, and survival in LGSC. METHODS: The National Cancer Database (NCDB) was queried for data between 2004 and 2015 on patients with LGSC. LGSC was inclusive of invasive, grade 1, serous carcinoma of the ovary, fallopian tube, or peritoneum. Patient demographics, insurance status, disease characteristics, treatment approach, and survival were evaluated. ANOVA, Chi Square, Kaplan-Meier, and Cox regression were used in the analysis. RESULTS: 3221 patients with LGSC were evaluated (89.5% White, 6.2% Black; 7.2% Hispanic, 92.8% non-Hispanic). Compared to Whites, Blacks were diagnosed younger (50.4 vs. 55.9 years, p < 0.01), received less chemotherapy (61.8% vs 67.0%, p = 0.04), and had less CA-125 elevation (OR 4.14 [1.26-13.57], p = 0.02). Compared to non-Hispanics, Hispanics were younger (49.5 vs. 55.8 years, p < 0.01) and received less chemotherapy (55% vs 67%, p < 0.001). In contrast to private insurance, government insurance was associated with a higher 30-day mortality (1.5% vs 0.01%, p < 0.001). Race/ethnicity were not predictive of OS, while older age (HR 1.013 [1.002-1.024], p = 0.03), advanced stage (HR 3.09 [2.15-4.43], p < 0.001), and government insurance (HR 2.33 [1.65-3.30], p < 0.001) were all independently associated with worse OS. CONCLUSIONS: Significant differences exist in the clinical characteristics, treatments, and outcomes of LGSC by sociodemographics, with Blacks and Hispanics being diagnosed younger and receiving less chemotherapy. Age, stage, and insurance status were predictive of overall survival.


Assuntos
Cistadenocarcinoma Seroso/etnologia , Cistadenocarcinoma Seroso/terapia , Disparidades em Assistência à Saúde/etnologia , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/terapia , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Cistadenocarcinoma Seroso/economia , Cistadenocarcinoma Seroso/patologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Disparidades em Assistência à Saúde/economia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Hispano-Americanos/estatística & dados numéricos , Humanos , Cobertura do Seguro , Pessoa de Meia-Idade , Programas Nacionais de Saúde , Neoplasias Ovarianas/economia , Neoplasias Ovarianas/patologia , Taxa de Sobrevida , Estados Unidos/epidemiologia , Adulto Jovem
20.
Cancer Cell ; 37(2): 226-242.e7, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32049047

RESUMO

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of ∼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of ∼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.


Assuntos
Células Epiteliais/patologia , Neoplasias das Tubas Uterinas/metabolismo , Tubas Uterinas/patologia , Neoplasias Ovarianas/patologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Epitélio/metabolismo , Epitélio/patologia , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/patologia , Tubas Uterinas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Heterogeneidade Genética , Humanos , Neoplasias Ovarianas/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA