RESUMO
The high-grade serous ovarian cancer (HGSOC) risk locus at chromosome 1p34.3 resides within a frequently amplified genomic region signifying the presence of an oncogene. Here, we integrate in silico variant-to-function analysis with functional studies to characterize the oncogenic potential of candidate genes in the 1p34.3 locus. Fine mapping of genome-wide association statistics identified candidate causal SNPs local to H3K27ac-demarcated enhancer regions that exhibit allele-specific binding for CTCF in HGSOC and normal fallopian tube secretory epithelium cells (FTSECs). SNP risk associations colocalized with eQTL for six genes (DNALI1, GNL2, RSPO1, SNIP1, MEAF6, and LINC01137) that are more highly expressed in carriers of the risk allele, and three (DNALI1, GNL2, and RSPO1) were upregulated in HGSOC compared to normal ovarian surface epithelium cells and/or FTSECs. Increased expression of GNL2 and MEAF6 was associated with shorter survival in HGSOC with 1p34.3 amplifications. Despite its activation of ß-catenin signaling, RSPO1 overexpression exerted no effects on proliferation or colony formation in our study of ovarian cancer and FTSECs. Instead, GNL2, MEAF6, and SNIP1 silencing impaired in vitro ovarian cancer cell growth. Additionally, GNL2 silencing diminished xenograft tumor formation, whereas overexpression stimulated proliferation and colony formation in FTSECs. GNL2 influences 60S ribosomal subunit maturation and global protein synthesis in ovarian cancer and FTSECs, providing a potential mechanism of how GNL2 upregulation might promote ovarian cancer development and mediate genetic susceptibility of HGSOC.
Assuntos
Cromossomos Humanos Par 1 , Cistadenocarcinoma Seroso/genética , Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Locos de Características Quantitativas , Alelos , Processamento Alternativo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Sequenciamento de Cromatina por Imunoprecipitação , Cistadenocarcinoma Seroso/patologia , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Elementos Facilitadores Genéticos , Feminino , Proteínas de Ligação ao GTP/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Xenoenxertos , Humanos , Camundongos , Gradação de Tumores , Razão de Chances , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Transcriptoma , População BrancaRESUMO
BACKGROUND: Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in ovarian carcinoma (OC). While the role of DOT1L in cancer and chemoresistance is acknowledged, its specific role in PARPi resistance remains unclear. This study aims to elucidate the molecular mechanism of DOT1L in PARPi resistance in OC patients. METHODS: This study analyzed the expression of DOT1L in PARPi-resistant cell lines compared to sensitive ones and correlated it with clinical outcomes in OC patients. Comprehensive in vitro and in vivo functional experiments were conducted using cellular and mouse models. Molecular investigations, including RNA sequencing, chromatin immunoprecipitation (ChIP) and Cleavage Under Targets and Tagmentation (CUT&Tag) assays, were employed to unravel the molecular mechanisms of DOT1L-mediated PARPi resistance. RESULTS: Our investigation revealed a robust correlation between DOT1L expression and clinical PARPi resistance in non-BRCA mutated OC cells. Upregulated DOT1L expression in PARPi-resistant tissues was associated with diminished survival in OC patients. Mechanistically, we identified that PARP1 directly binds to the DOT1L gene promoter, promoting transcription independently of its enzyme activity. PARP1 trapping induced by PARPi treatment amplified this binding, enhancing DOT1L transcription and contributing to drug resistance. Sequencing analysis revealed that DOT1L plays a crucial role in the transcriptional regulation of PLCG2 and ABCB1 via H3K79me2. This established the PARP1-DOT1L-PLCG2/ABCB1 axis as a key contributor to PARPi resistance. Furthermore, we discovered that combining a DOT1L inhibitor with PARPi demonstrated a synergistic effect in both cell line-derived xenograft mouse models (CDXs) and patient-derived organoids (PDOs). CONCLUSIONS: Our results demonstrate that DOT1L is an independent prognostic marker for OC patients. The PARP1-DOT1L/H3K79me2-PLCG2/ABCB1 axis is identified as a pivotal contributor to PARPi resistance. Targeted inhibition of DOT1L emerges as a promising therapeutic strategy for enhancing PARPi treatment outcomes in OC patients.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Feminino , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Animais , Camundongos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Prognóstico , Histona-Lisina N-MetiltransferaseRESUMO
A Japanese clinical trial (JGOG3016) showed that dose-dense weekly paclitaxel in combination with carboplatin extensively prolonged overall survival (OS) in patients with advanced ovarian cancer. However, in other clinical trials, dose-dense paclitaxel regimens were not superior to triweekly paclitaxel regimens. In this study, causal tree analysis was applied to explore subpopulations with different treatment effects of dose-dense paclitaxel in a data-driven approach. The 587 participants with stage II-IV ovarian cancer in the JGOG3016 trial were used for model development. The primary endpoint was treatment effect in terms of 3-year OS in patients receiving dose-dense vs. conventional paclitaxel therapies. In patients <50 years, the 3-year OS was similar in both groups; however, it was higher in the dose-dense group in patients ≥50 years. Dose-dense paclitaxel showed strong positive treatment effects in patients ≥50 years with stage II/III disease, BMI <23 kg/m2, non-CC/MC, and residual tumor ≥1 cm. In contrast, although there was no significant difference in OS; the 3-year OS rate was 23% lower in dose-dense paclitaxel than conventional paclitaxel in patients ≥60 years with stage IV cancer. Patients in this group had a particularly lower performance status than other groups. Our causal tree analysis suggested that poor prognosis groups represented by residual tumor tissue ≥1 cm benefit from dose-dense paclitaxel, whereas elderly patients with advanced disease and low-performance status are negatively impacted by dose-dense paclitaxel. These subpopulations will be of interest to future validation studies. Personalized treatments based on clinical features are expected to improve advanced ovarian cancer prognosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina , Neoplasias Ovarianas , Paclitaxel , Humanos , Feminino , Paclitaxel/administração & dosagem , Carboplatina/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , Idoso , Adulto , Estadiamento de Neoplasias , Resultado do Tratamento , Heterogeneidade da Eficácia do TratamentoRESUMO
We analyzed variations in the epidermal growth factor receptor (EGFR) gene and 5'-upstream region to identify potential molecular predictors of treatment response in primary epithelial ovarian cancer. Tumor tissues collected during debulking surgery from the prospective multicenter OVCAD study were investigated. Copy number variations in the human endogenous retrovirus sequence human endogenous retrovirus K9 (HERVK9) and EGFR Exons 7 and 9, as well as repeat length and loss of heterozygosity of polymorphic CA-SSR I and relative EGFR mRNA expression were determined quantitatively. At least one EGFR variation was observed in 94% of the patients. Among the 30 combinations of variations discovered, enhanced platinum sensitivity (n = 151) was found dominantly with HERVK9 haploidy and Exon 7 tetraploidy, overrepresented among patients with survival ≥120 months (24/29, p = .0212). EGFR overexpression (≥80 percentile) was significantly less likely in the responders (17% vs. 32%, p = .044). Multivariate Cox regression analysis, including age, FIGO stage, and grade, indicated that the patients' subgroup was prognostically significant for CA-SSR I repeat length <18 CA for both alleles (HR 0.276, 95% confidence interval 0.109-0.655, p = .001). Although EGFR variations occur in ovarian cancer, the mRNA levels remain low compared to other EGFR-mutated cancers. Notably, the inherited length of the CA-SSR I repeat, HERVK9 haploidy, and Exon 7 tetraploidy conferred three times higher odds ratio to survive for more than 10 years under therapy. This may add value in guiding therapies if determined during follow-up in circulating tumor cells or circulating tumor DNA and offers HERVK9 as a potential therapeutic target.
Assuntos
Cromossomos Humanos Par 7 , Variações do Número de Cópias de DNA , Receptores ErbB , Neoplasias Ovarianas , Humanos , Feminino , Receptores ErbB/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Pessoa de Meia-Idade , Cromossomos Humanos Par 7/genética , Estudos Prospectivos , Idoso , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Adulto , Retroelementos/genética , Fenótipo , Resistencia a Medicamentos Antineoplásicos/genética , Retrovirus Endógenos/genética , Perda de HeterozigosidadeRESUMO
Use of menopausal hormone therapy (MHT) prior to an epithelial ovarian cancer (EOC) diagnosis has been suggested to be associated with improved survival. In a recent nationwide cohort study, we found that prediagnostic long-term MHT use, especially estrogen therapy (ET), was associated with improved long-term survival in women with nonlocalized EOC. Our aim was to investigate the influence of prediagnostic MHT use on long-term survival among women with localized EOC in the same nationwide study. Our study cohort comprised all women aged 50 years or older with an EOC diagnosis in Denmark 2000-2014 (n = 2097) identified from the Extreme study. We collected information on usage of systemic ET and estrogen plus progestin therapy (EPT) from the Danish National Prescription Registry. By using pseudo-values, 5- and 10-year absolute and relative survival probabilities were estimated with 95% confidence intervals (CIs) while adjusting for histology, comorbidity, and income. Relative survival probabilities >1 indicate better survival. The 5-year absolute survival probabilities were 61% and 56%, respectively, among women who were nonusers and users of prediagnostic MHT, whereas these numbers were 46% and 41%, respectively, regarding 10-year survival. Use of MHT was not significantly associated with an improved 5- or 10-year survival in women with localized EOC (5-year relative survival probability = 0.95, 95% CI: 0.89-1.02; 10-year relative survival probability = 0.92, 95% CI: 0.84-1.02). Similar findings were seen for systemic ET or EPT use. Our findings do not suggest a positive benefit from prediagnostic MHT use on long-term survival of localized EOC.
Assuntos
Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Humanos , Feminino , Pessoa de Meia-Idade , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Dinamarca/epidemiologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Idoso , Terapia de Reposição de Estrogênios/efeitos adversos , Terapia de Reposição de Estrogênios/métodos , Sistema de Registros , Estudos de Coortes , Menopausa , Estrogênios/administração & dosagem , Progestinas/uso terapêutico , Progestinas/administração & dosagemRESUMO
BACKGROUND: This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC). METHODS: Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1-21) plus niraparib 200 mg daily (days 1-28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator-determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super-responders (complete response or those with progression-free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized. RESULTS: The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%-53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%-44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively. CONCLUSIONS: Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Ftalazinas , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Idoso , Adulto , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Ftalazinas/uso terapêutico , Ftalazinas/administração & dosagem , Indazóis/uso terapêutico , Indazóis/administração & dosagem , Proteína BRCA1/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Idoso de 80 Anos ou mais , Platina/uso terapêutico , Platina/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Proteína BRCA2/genética , Intervalo Livre de Progressão , AzetidinasRESUMO
BACKGROUND: Other than for breast cancer, endocrine therapy has not been highly effective for gynecologic cancers. Endocrine therapy resistance in estrogen receptor positive gynecologic cancers is still poorly understood. In this retrospective study, we examined the estrogen receptor (ER) signaling pathway activities of breast, ovarian, endometrial, and cervical cancers to identify those that may predict endocrine therapy responsiveness. METHODS: Clinical and genomic data of women with breast and gynecological cancers were downloaded from cBioPortal for Cancer Genomics. Estrogen receptor alpha (ESR1) expression level and sample-level pathway enrichment scores (EERES) were calculated to classify patients into four groups (low/high ESR1 and low/high EERES). Correlation between ESR1/EERES score and survival was further validated with RNAseq data from low-grade serous ovarian cancer. Pathway analyses were performed among different ESR1/EERES groups to identify genes that correlate with endocrine resistance, which are validated using Cancer Cell Line Encyclopedia gene expression and Genomics of Drug Sensitivity in Cancer data. RESULTS: We identified a novel combined prognostic value of ESR1 expression and the corresponding estrogen response signaling (EERES score) for breast cancer. The combined prognostic value (ESR1/EERES) may be applicable to other gynecologic cancers. More importantly, we discovered that ER signaling can cross-regulate MEK pathway activation. We identified downstream genes in the MEK pathway (EPHA2, INAVA, MALL, MPZL2, PCDH1, and TNFRSF21) that are potential endocrine therapy response biomarkers. CONCLUSION: This study demonstrated that targeting both the ER and the ER signaling activity related MEK pathway may aid the development of endocrine therapy strategies for personalized medicine.
Assuntos
Receptor alfa de Estrogênio , Humanos , Feminino , Prognóstico , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Estudos Retrospectivos , Sistema de Sinalização das MAP Quinases/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Resistencia a Medicamentos Antineoplásicos/genética , Transdução de Sinais , Regulação Neoplásica da Expressão Gênica , Antineoplásicos Hormonais/uso terapêutico , Linhagem Celular Tumoral , Neoplasias dos Genitais Femininos/genética , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/metabolismo , Neoplasias dos Genitais Femininos/patologia , Neoplasias dos Genitais Femininos/mortalidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidadeRESUMO
BACKGROUND: In women, ovarian cancer is the eighth most frequent cancer in incidence and mortality. It is often diagnosed at advanced stages; relapses are frequent, with a poor prognosis. When platinum resistant, subsequent lines of chemotherapy are of limited effect and often poorly tolerated, leading to quality of life deterioration. Various studies suggest a hormonal role in ovarian carcinogenesis, with a rationale for endocrine therapy in these cancers. PATIENTS AND METHODS: This multicenter, retrospective study assessed the use of endocrine treatment for high-grade ovarian epithelial carcinomas treated between 2010 and 2020. RESULTS: Eighty-one patients with ovarian cancers were included. The median duration of platinum sensitivity was 29 months. We observed a 35% disease control rate with endocrine therapy, and 10% reported symptom improvement. For 19 patients (23.5%), the disease was stabilized for more than 6 months. Median overall survival from diagnosis was 62.6 months. Regarding endocrine therapy predictive factors of response, in a multivariate analysis, 3 factors were statistically significant in favoring progression-free survival: platinum sensitivity (Pâ =â .021), an R0 surgical resection (Pâ =â .020), and the indication for hormone therapy being maintenance therapy (Pâ =â .002). CONCLUSION: This study shows real-life data on endocrine therapy in ovarian cancer. As it is a low-cost treatment with many advantages such as its oral administration and its safety, it may be an option to consider. A perspective lies in the search for cofactors to aim as future therapeutic targets to improve the effectiveness of hormone treatment by means of combination therapy.
Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Adulto , Idoso de 80 Anos ou mais , Qualidade de Vida , Antineoplásicos Hormonais/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/mortalidadeRESUMO
BACKGROUND: Treatment for patients with recurrent ovarian cancer has been mainly based on systemic therapy. The role of secondary cytoreductive surgery is unclear. METHODS: We randomly assigned patients with recurrent ovarian cancer who had a first relapse after a platinum-free interval (an interval during which no platinum-based chemotherapy was used) of 6 months or more to undergo secondary cytoreductive surgery and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Patients were eligible if they presented with a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, defined as an Eastern Cooperative Oncology Group performance-status score of 0 (on a 5-point scale, with higher scores indicating greater disability), ascites of less than 500 ml, and complete resection at initial surgery. A positive AGO score is used to identify patients in whom a complete resection might be achieved. The primary end point was overall survival. We also assessed quality of life and prognostic factors for survival. RESULTS: A total of 407 patients underwent randomization: 206 were assigned to cytoreductive surgery and chemotherapy, and 201 to chemotherapy alone. A complete resection was achieved in 75.5% of the patients in the surgery group who underwent the procedure. The median overall survival was 53.7 months in the surgery group and 46.0 months in the no-surgery group (hazard ratio for death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.02). Patients with a complete resection had the most favorable outcome, with a median overall survival of 61.9 months. A benefit from surgery was seen in all analyses in subgroups according to prognostic factors. Quality-of-life measures through 1 year of follow-up did not differ between the two groups, and we observed no perioperative mortality within 30 days after surgery. CONCLUSIONS: In women with recurrent ovarian cancer, cytoreductive surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone. (Funded by the AGO Study Group and others; DESKTOP III ClinicalTrials.gov number, NCT01166737.).
Assuntos
Antineoplásicos/uso terapêutico , Procedimentos Cirúrgicos de Citorredução , Recidiva Local de Neoplasia/cirurgia , Neoplasias Ovarianas/cirurgia , Idoso , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Modelos de Riscos Proporcionais , Qualidade de Vida , Análise de SobrevidaRESUMO
PURPOSE: The purpose of this study was to assess the association between race/ethnicity and all-cause mortality among women with advanced-stage ovarian cancer who received systemic therapy. METHODS: We analyzed data from the National Cancer Database on women diagnosed with advanced-stage ovarian cancer from 2004 to 2015 who received systemic therapy. Race/ethnicity was categorized as Non-Hispanic (NH) White, NH-Black, Hispanic, NH-Asian/Pacific Islander, and Other. Income and education were combined to form a composite measure of socioeconomic status (SES) and categorized into low-, mid-, and high-SES. Multivariable Cox proportional hazards models were used to assess whether race/ethnicity was associated with the risk of death after adjusting for sociodemographic, clinical, and treatment factors. Additionally, subgroup analyses were conducted by SES, age, and surgery receipt. RESULTS: The study population comprised 53,367 women (52.4% ages ≥ 65 years, 82% NH-White, 8.7% NH-Black, 5.7% Hispanic, and 2.7% NH-Asian/Pacific Islander) in the analysis. After adjusting for covariates, the NH-Black race was associated with a higher risk of death versus NH-White race (aHR: 1.12; 95% CI: 1.07,1.18), while Hispanic ethnicity was associated with a lower risk of death compared to NH-White women (aHR: 0.87; 95% CI: 0.80, 0.95). Furthermore, NH-Black women versus NH-White women had an increased risk of mortality among those with low-SES characteristics (aHR:1.12; 95% CI:1.03-1.22) and mid-SES groups (aHR: 1.13; 95% CI:1.05-1.21). CONCLUSIONS: Among women with advanced-stage ovarian cancer who received systemic therapy, NH-Black women experienced poorer survival compared to NH-White women. Future studies should be directed to identify drivers of ovarian cancer disparities, particularly racial differences in treatment response and surveillance.
Assuntos
Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Determinantes Sociais da Saúde , Disparidades Socioeconômicas em Saúde , Feminino , Humanos , Carcinoma Epitelial do Ovário/epidemiologia , Carcinoma Epitelial do Ovário/etnologia , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/terapia , Etnicidade/estatística & dados numéricos , Hispânico ou Latino/estatística & dados numéricos , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/terapia , População Branca/estatística & dados numéricos , Negro ou Afro-Americano/estatística & dados numéricos , Nativo Asiático-Americano do Havaí e das Ilhas do Pacífico/estatística & dados numéricos , Determinantes Sociais da Saúde/economia , Determinantes Sociais da Saúde/etnologia , Determinantes Sociais da Saúde/estatística & dados numéricosRESUMO
PURPOSE: High-grade serous ovarian cancer (HGSC) is the most common ovarian cancer subtype. Parity is an important risk-reducing factor, but the underlying mechanism behind the protective effect is unclear. Our aim was to study if the expression of hormones and proteins involved in pregnancy were affected by the woman's parity status, and if they may be associated with tumor stage and survival. METHODS: We evaluated expression of progesterone receptor (PR), progesterone receptor membrane component 1 (PGRMC1), relaxin-2, and transforming growth factor beta 1 (TGFß1) in tumor tissue from 92 women with HGSC parous (n = 73) and nulliparous (n = 19). Key findings were then evaluated in an independent expansion cohort of 49 patients. Survival rates by hormone/protein expression were illustrated using the Kaplan-Meier method. The independent prognostic value was tested by Cox regression, using models adjusted for established poor-prognostic factors (age at diagnosis, FIGO stage, type of surgery, and macroscopic residual tumor after surgery). RESULTS: HGSC tumors from parous women were PR positive (≥ 1% PR expression in tumor cells) more often than tumors from nulliparous women (42% vs. 16%; p-value 0.04), and having more children was associated with developing PR positive tumors [i.e., ≥ 3 children versus nulliparity, adjusted for age at diagnosis and stage: OR 4.31 (95% CI 1.12-19.69)]. A similar result was seen in the expansion cohort. Parity status had no impact on expression of PGRMC1, relaxin-2 and TGFß1. No associations were seen with tumor stage or survival. CONCLUSION: Tumors from parous women with HGSC expressed PR more often than tumors from nulliparous women, indicating that pregnancies might possibly have a long-lasting impact on ovarian cancer development.
Assuntos
Neoplasias Ovarianas , Paridade , Receptores de Progesterona , Humanos , Feminino , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Gravidez , Pessoa de Meia-Idade , Adulto , Receptores de Progesterona/metabolismo , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/mortalidade , Prognóstico , Idoso , Proteínas de Membrana/metabolismo , Gradação de Tumores , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Relaxina/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: Inherited variations in DNA double-strand break (DSB) repair pathway are known to influence ovarian cancer occurrence, progression and treatment response. Despite its significance, survival-associated genetic variants within the DSB pathway remain underexplored. METHODS: In the present study, we performed a two-phase analysis of 19,290 single-nucleotide polymorphisms (SNPs) in 199 genes in the DSB repair pathway from a genome-wide association study (GWAS) dataset and explored their associations with overall survival (OS) in 1039 Han Chinese epithelial ovarian carcinoma (EOC) patients. After utilizing multivariate Cox regression analysis with bayesian false-discovery probability for multiple test correction, significant genetic variations were identified and subsequently underwent functional prediction and validation. RESULTS: We discovered a significant association between poor overall survival and the functional variant GEN1 rs56070363 C > T (CT + TT vs. TT, adjusted hazard ratio (HR) = 2.50, P < 0.001). And the impact of GEN1 rs56070363 C > T on survival was attributed to its reduced binding affinity to hsa-miR-1287-5p and the resultant upregulation of GEN1 mRNA expression. Overexpression of GEN1 aggregated EOC cell proliferation, invasion and migration presumably by influencing the expression of immune inhibitory factors, thereby elevating the proportion of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and then constructing an immunosuppressive tumor microenvironment. CONCLUSIONS: In conclusion, GEN1 rs56070363 variant could serve as a potential predictive biomarker and chemotherapeutic target for improving the survival of EOC patients.
Assuntos
Carcinoma Epitelial do Ovário , Resolvases de Junção Holliday , Neoplasias Ovarianas , Polimorfismo de Nucleotídeo Único , Feminino , Humanos , Pessoa de Meia-Idade , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , China , População do Leste Asiático/genética , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla , Estimativa de Kaplan-Meier , MicroRNAs/genética , Invasividade Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Prognóstico , Análise de Sobrevida , Resolvases de Junção Holliday/genéticaRESUMO
AIMS: Mucinous ovarian carcinoma (MOC) is a rare ovarian cancer histotype with generally good prognosis when diagnosed at an early stage. However, MOC with the infiltrative pattern of invasion has a worse prognosis, although to date studies have not been large enough to control for covariables. Data on reproducibility of classifying the invasion pattern are limited, as are molecular correlates for infiltrative invasion. We hypothesized that the invasion pattern would be associated with an aberrant tumour microenvironment. METHODS AND RESULTS: Four subspecialty pathologists assessed interobserver reproducibility of the pattern of invasion in 134 MOC. Immunohistochemistry on fibroblast activation protein (FAP) and THBS2 was performed on 98 cases. Association with survival was tested using Cox regression. The average interobserver agreement for the infiltrative pattern was moderate (kappa 0.60, agreement 86.3%). After reproducibility review, 24/134 MOC (18%) were determined to have the infiltrative pattern and this was associated with a higher risk of death, independent of FIGO stage, grade, and patient age in a time-dependent manner (hazard ratio [HR] = 10.2, 95% confidence interval [CI] 3.0-34.5). High stromal expression of FAP and THBS2 was more common in infiltrative MOC (FAP: 60%, THBS2: 58%, both P < 0.001) and associated with survival (multivariate HR for FAP: 1.5 [95% CI 1.1-2.1] and THBS2: 1.91 [95% CI 1.1-3.2]). CONCLUSIONS: The pattern of invasion should be included in reporting for MOC due to the strong prognostic implications. We highlight the histological features that should be considered to improve reproducibility. FAP and THBS2 are associated with infiltrative invasion in MOC.
Assuntos
Adenocarcinoma Mucinoso , Biomarcadores Tumorais , Endopeptidases , Neoplasias Ovarianas , Trombospondinas , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Gelatinases/metabolismo , Gelatinases/análise , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Proteínas de Membrana/metabolismo , Invasividade Neoplásica , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/metabolismo , Prognóstico , Reprodutibilidade dos Testes , Serina Endopeptidases/metabolismo , Trombospondinas/metabolismo , Microambiente TumoralRESUMO
BACKGROUND: Ovarian cancer (OC) is a gynecological malignancy tumor with high recurrence and mortality rates. Programmed cell death (PCD) is an essential regulator in cancer metabolism, whose functions are still unknown in OC. Therefore, it is vital to determine the prognostic value and therapy response of PCD-related genes in OC. METHODS: By mining The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Genecards databases, we constructed a prognostic PCD-related genes model and performed Kaplan-Meier (K-M) analysis and Receiver Operating Characteristic (ROC) curve for its predictive ability. A nomogram was created via Cox regression. We validated our model in train and test sets. Quantitative real-time PCR (qRT-PCR) was applied to identify the expression of our model genes. Finally, we analyzed functional analysis, immune infiltration, genomic mutation, tumor mutational burden (TMB) and drug sensitivity of patients in low- and high-risk group based on median scores. RESULTS: A ten-PCD-related gene signature including protein phosphatase 1 regulatory subunit 15 A (PPP1R15A), 8-oxoguanine-DNA glycosylase (OGG1), HECT and RLD domain containing E3 ubiquitin protein ligase family member 1 (HERC1), Caspase-2.(CASP2), Caspase activity and apoptosis inhibitor 1(CAAP1), RB transcriptional corepressor 1(RB1), Z-DNA binding protein 1 (ZBP1), CD3-epsilon (CD3E), Clathrin heavy chain like 1(CLTCL1), and CCAAT/enhancer-binding protein beta (CEBPB) was constructed. Risk score performed well with good area under curve (AUC) (AUC3 - year =0.728, AUC5 - year = 0.730). The nomogram based on risk score has good performance in predicting the prognosis of OC patients (AUC1 - year =0.781, AUC3 - year =0.759, AUC5 - year = 0.670). Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that the erythroblastic leukemia viral oncogene homolog (ERBB) signaling pathway and focal adhesion were enriched in the high-risk group. Meanwhile, patients with high-risk scores had worse OS. In addition, patients with low-risk scores had higher immune-infiltrating cells and enhanced expression of checkpoints, programmed cell death 1 ligand 1 (PD-L1), indoleamine 2,3-dioxygenase 1 (IDO-1) and lymphocyte activation gene-3 (LAG3), and were more sensitive to A.443,654, GDC.0449, paclitaxel, gefitinib and cisplatin. Finally, qRT-PCR confirmed RB1, CAAP1, ZBP1, CEBPB and CLTCL1 over-expressed, while PPP1R15A, OGG1, CASP2, CD3E and HERC1 under-expressed in OC cell lines. CONCLUSION: Our model could precisely predict the prognosis, immune status and drug sensitivity of OC patients.
Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Prognóstico , Biomarcadores Tumorais/genética , Nomogramas , Regulação Neoplásica da Expressão Gênica , Apoptose/genética , Pessoa de Meia-Idade , Perfilação da Expressão Gênica , Estimativa de Kaplan-Meier , Bases de Dados Genéticas , Curva ROCRESUMO
BACKGROUND: Recent studies showed heterogeneity in stage IVB patients. However, few studies focused on the prognosis of supraclavicular metastatic ovarian cancer. This study aimed to explore the prognostic factors and the role of primary debulking in IVB ovarian cancer patients with supraclavicular lymph node metastasis. METHODS: We retrospectively analyzed patients newly diagnosed as primary epithelial ovarian cancer with supraclavicular lymph node metastasis from January 2015 to July 2020. Supraclavicular lymph node metastasis was defined as either the pathological diagnosis by supraclavicular lymph node biopsy, or the radiological diagnosis by positron emission tomography-computed tomography (PET-CT). RESULTS: In 51 patients, 37 was diagnosed with metastatic supraclavicular lymph nodes by histology, 46 by PET-CT, and 32 by both methods. Forty-four (86.3%) with simultaneous metastatic paraaortic lymph nodes (PALNs) by imaging before surgery or neoadjuvant chemotherapy were defined as "continuous-metastasis type", while the other 7 (13.7%) defined as "skip-metastasis type". Nineteen patients were confirmed with metastatic PALNs by histology. Thirty-four patients were investigated for BRCA mutation, 17 had germline or somatic BRCA1/2 mutations (g/sBRCAm). With a median follow-up of 30.0 months (6.3-63.4 m), 16 patients (31.4%) died. The median PFS and OS of the cohort were 17.3 and 48.9 months. Survival analysis showed that "continuous-metastasis type" had longer OS and PFS than "skip-metastasis type" (OS: 50.0/26.6 months, PFS: 18.5/7.2months, p=0.005/0.002). BRCA mutation carriers also had longer OS and PFS than noncarriers (OS: 57.4 /38.5 m, p=0.031; PFS: 23.6/15.2m, p=0.005). Multivariate analysis revealed only metastatic PALNs was independent prognostic factor for OS (p=0.040). Among "continuous-metastasis type" patients, 22 (50.0%) achieved R0 abdominopelvic debulking, who had significantly longer OS (55.3/42.3 months, p =0.034) than those with residual abdominopelvic tumors. CONCLUSIONS: In stage IVB ovarian cancer patients with supraclavicular lymph nodes metastasis, those defined as "continuous-metastasis type" with positive PALNs had better prognosis. For them, optimal abdominopelvic debulking had prognostic benefit, although metastatic supraclavicular lymph nodes were not resected. Higher BRCA mutation rate than the general population of ovarian cancer patients was observed in patients with IVB supraclavicular lymph node metastasis, leading to better survival as expected.
Assuntos
Procedimentos Cirúrgicos de Citorredução , Metástase Linfática , Estadiamento de Neoplasias , Neoplasias Ovarianas , Humanos , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Prognóstico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/mortalidade , Procedimentos Cirúrgicos de Citorredução/métodos , Adulto , Idoso , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/mortalidade , Linfonodos/patologia , Linfonodos/cirurgia , China/epidemiologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Proteína BRCA1/genética , População do Leste AsiáticoRESUMO
BACKGROUND: The modeled CA-125 elimination constant K (KELIM) is a potential marker of tumor chemosensitivity in ovarian cancer patients treated with neoadjuvant chemotherapy (NACT) before interval surgery. The objective of this study was to externally validate the KELIM (rate of elimination of CA-125) score in patients with high-grade serous ovarian cancer (HGSC) undergoing NACT and explore its relation to the completeness of IDS and survival. METHODS: The study was based on a retrospective cohort of 133 patients treated for advanced HGSC, International Federation of Gynecology and Obstetrics (FIGO) stages III-IV, with neoadjuvant chemotherapy, folllowed by interval surgery, in two centres in China. CA-125 concentrations at baseline and during neoadjuvant chemotherapy were collected. We used standardized (std) KELIM for subsequent analysis. Clinicopathologic parameters were collected, and KaplanâMeier survival analyses were performed for PFS and OS. RESULTS: KELIM was an independent predictor of the probability of complete surgery and survival in our cohort. The median std KELIM score of patients with complete surgery was significantly higher than that of patients with incomplete IDS (1.20 vs. 0.71, P < 0.001). Multivariate analysis showed that a std KELIM score ≥0.925 was an independent predictive factor for achieving complete resection (OR = 5.480; 95% CI, 2.409-12.466, P < 0.001) and better PFS (HR = 0.544; 95% CI: 0.349-0.849, P = 0.007) and OS (HR = 0.484; 95% CI: 0.251-0.930, P = 0.030). CONCLUSIONS: The tumor-primary tumor chemosensitivity, assessed by the modeled CA-125 KELIM, calculated during NACT, is a major parameter to consider for decision-making regarding IDS attempts and predicting patient survival.
Assuntos
Antígeno Ca-125 , Procedimentos Cirúrgicos de Citorredução , Terapia Neoadjuvante , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/sangue , Estudos Retrospectivos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Antígeno Ca-125/sangue , Idoso , China , Adulto , Quimioterapia Adjuvante/métodos , Prognóstico , Estadiamento de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estimativa de Kaplan-Meier , Biomarcadores Tumorais/sangueRESUMO
PURPOSE: To investigate the role of prognostic genes related to cisplatin resistance in ovarian cancer during disease progression. METHOD: The gene expression profile of the NCI-60 cell line was acquired through comprehensive analysis of the GEO database accession GSE116439. We performed a thorough analysis of gene expression differences in samples from seven individuals exposed to cisplatin concentrations of 0 nM compared to seven samples exposed to 15000 nM over a 24-h period. Key genes were initially identified through LASSO regression, followed by their enrichment through differential gene function analysis (GO) and pathway enrichment analysis (KEGG). Subsequently, a prognostic risk model was established for these key genes. The prognostic model's performance was assessed through K-M survival curves and ROC curves. To examine the variance in immune cell infiltration between the high and low-risk groups, CIBERSORTx analysis was employed. Finally, validation of prognostic gene expression in cisplatin-resistant ovarian cancer was carried out using clinical samples, employing RT-qPCR and Western Blot techniques. RESULTS: A total of 132 differential genes were found between cisplatin resistance and control group, and 8 key prognostic genes were selected by analysis, namely VPS13B, PLGRKT, CDKAL1, TBC1D22A, TAP1, PPP3CA, CUX1 and PPP1R15A. The efficacy of the risk assessment model derived from prognostic biomarkers, as indicated by favorable performance on both Kaplan-Meier survival curves and ROC curves. Significant variations in the abundance of Macrophages M1, T cells CD4 memory resting, T cells follicular helper, and T cells gamma delta were observed between the high and low-risk groups. To further validate our findings, RT-qPCR and Western Blot analyses were employed, confirming differential expression of the identified eight key genes between the two groups. CONCLUSION: VPS13B, TBC1D22A, PPP3CA, CUX1 and PPP1R15A were identified as poor prognostic genes of cisplatin resistance in ovarian cancer, while PLGRKT, CDKAL1 and TAP1 were identified as good prognostic genes. This offers a novel perspective for future advancements in ovarian cancer treatment, suggesting potential avenues for the development of new therapeutic targets.
Assuntos
Cisplatino , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas , Humanos , Feminino , Cisplatino/uso terapêutico , Cisplatino/farmacologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Prognóstico , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Linhagem Celular Tumoral , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , TranscriptomaRESUMO
BACKGROUND: Trabectedin in combination with pegylated liposomal doxorubicin (PLD) is approved for the treatment of patients with platinum-sensitive relapsed ovarian cancer. Nevertheless, there is currently limited information regarding this treatment in elderly patients with ovarian cancer in a real-world setting. METHODS: This observational and multicentric study retrospectively evaluated trabectedin plus PLD in a real-world setting treatment of elderly patients diagnosed with platinum-sensitive relapsed ovarian cancer, treated according to the Summary of Product Characteristics (SmPC) from 15 GEICO-associated hospitals. Patients ≥ 70 years old at the time of treatment initiation and platinum-free intervals ≥ 6 months were considered eligible. RESULTS: Forty-three patients with a median age of 74.0 years were treated between January 1st, 2015, and December 31st, 2019 in 15 Spanish centers. Four patients achieved complete response (9.3%), 14 (32.6%) partial response, and 13 (30.2%) stable disease as the best radiological response. In the analysis of biological overall response according to CA125 serum levels (i.e., Rustin criteria), 14 responded to the treatment (32.6%), 11 responded and normalized (25.6%), three patients stabilized (7.0%) and three progressed (7.0%). Median progression-free survival (PFS) and overall survival (OS) in the study population were 7.7 and 19.5 months, respectively. The most common grade 3/4 adverse events were neutropenia (n = 8, 18.7%) and asthenia (n = 5, 11.6%). CONCLUSIONS: This analysis demonstrated that trabectedin combined with PLD is a feasible and effective treatment in elderly patients with platinum-sensitive relapsed ovarian cancer, showing an acceptable safety profile, which is crucial in the palliative treatment of these patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Doxorrubicina , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Polietilenoglicóis , Trabectedina , Humanos , Trabectedina/uso terapêutico , Trabectedina/administração & dosagem , Feminino , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/administração & dosagem , Idoso , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Estudos Retrospectivos , Polietilenoglicóis/uso terapêutico , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso de 80 Anos ou mais , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado do TratamentoRESUMO
Ovarian cancer (OC) is a global health problem, and the mortality-to-incidence ratio is expected to increase, especially in low- and middle-income countries. These regions face disparities in access to OC care, including lack of awareness, limited access to genetic and tumor testing, paucity of surgical expertise, time to approval of novel therapeutics, and treatment costs. By addressing these inequities, the core aim of this paper is to promote action through collaboration in order to overcome these barriers and promote health equity in OC management and treatment.
Assuntos
Acessibilidade aos Serviços de Saúde , Disparidades em Assistência à Saúde , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/mortalidade , Disparidades em Assistência à Saúde/estatística & dados numéricos , Países em Desenvolvimento , Saúde GlobalRESUMO
OBJECTIVES: Ovarian tumors in the pediatric population are rare. The incidence and frequency of subtypes differ between children and adults. Although not all tumors are aggressive, they may still lead to morbidity. The goal of this study was a comprehensive review of malignant ovarian tumors in children and adolescents diagnosed and registered in Sweden. METHODS: Individuals were identified through a search in the National Cancer Register, limited for ages 0-19, years 1970-2014. Stored tumor diagnostic material from regional biobanks was retrieved and reviewed. RESULTS: The study includes 345 individuals with ovarian tumors and 70.7% of them were between 15 and 19 years at time of diagnosis. No differences in incidence over time or geographic location were identified. The average follow-up time was 21.2 years and 5-year survival was 88.4%. Survival was similar in the different time periods, except for 1970-1979. Review was possible for 260 cases, resulting in 85 epithelial tumors, 121 GCTs, 47 SCSTs and 7 others. For age 0-4 years SCSTs dominated (85.7%), for 5-9- and 10-14-years GCTs dominated (70,8% and 75.0% respectively), and for age 15-19 years epithelial tumors dominated (43.8%). There was a strong agreement between review diagnosis and original diagnosis (Cohen's κ 0.944). Differentiating between entities within the sex cord-stromal group posed the biggest diagnostic challenge. CONCLUSIONS: Ovarian tumors in children and adolescents are rare and distinct from their adult counterparts regarding incidence and frequency. There was a strong concurrence between original and review diagnoses. The greatest diagnostic difficulty was subtyping of epithelial tumors and differentiating between tumors within the SCST group.