RESUMO
In this study, we aimed to test whether prognostic biomarkers can achieve a clinically relevant stratification of patients with stage I ovarian clear cell carcinoma (OCCC) and to survey the expression of 10 selected actionable targets (theranostic biomarkers) in stage II to IV cases. From the population-based Alberta Ovarian Tumor Type study, 160 samples of OCCC were evaluated by immunohistochemistry and/or silver-enhanced in situ hybridization for the status of 5 prognostic (p53, p16, IGF2BP3, CCNE1, FOLR1) and 10 theranostic biomarkers (ALK, BRAF V600E, ERBB2, ER, MET, MMR, PR, ROS1, NTRK1-3, VEGFR2). Kaplan-Meier survival analyses were performed. Cases with abnormal p53 or combined p16/IFG2BP3 abnormal expression identified a small subset of patients (6/54 cases) with stage I OCCC with an aggressive course (5-yr ovarian cancer-specific survival of 33.3%, compared with 91.5% in the other stage I cases). Among theranostic targets, ERBB2 amplification was present in 11/158 (7%) of OCCC, while MET was ubiquitously expressed in OCCC similar to a variety of normal control tissues. ER/PR showed a low prevalence of expression. No abnormal expression was detected for any of the other targets. We propose a combination of 3 biomarkers (p53, p16, IGF2BP3) to predict prognosis and the potential need for adjuvant therapy for patients with stage I OCCC. This finding requires replication in larger cohorts. In addition, OCCC could be tested for ERBB2 amplification for inclusion in gynecological basket trials targeting this alteration.
Assuntos
Adenocarcinoma de Células Claras , Neoplasias Ovarianas , Adenocarcinoma de Células Claras/diagnóstico , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/terapia , Biomarcadores Tumorais/análise , Feminino , Receptor 1 de Folato , Humanos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/terapia , Medicina de Precisão , Prognóstico , Proteínas Proto-OncogênicasRESUMO
BACKGROUND: Anti-microtubule agents are widely used to treat ovarian cancers, but the efficacy is often compromised by drug resistance. We investigated co-targeting the actin/tropomyosin cytoskeleton and microtubules to increase treatment efficacy in ovarian cancers and potentially overcome resistance. METHODS: The presence of tropomyosin-3.1 (Tpm3.1) was examined in clinical specimens from ovarian cancer patients using immunohistochemistry. Combinatorial effects of an anti-Tpm3.1 compound, ATM-3507, with vinorelbine and paclitaxel were evaluated in ovarian cancer cells via MTS and apoptosis assays. The mechanisms of action were established using live- and fixed-cell imaging and protein analysis. RESULTS: Tpm3.1 is overexpressed in 97% of tumour tissues (558 of 577) representing all histotypes of epithelial ovarian cancer. ATM-3507 displayed synergy with both anti-microtubule agents to reduce cell viability. Only vinorelbine synergised with ATM-3507 in causing apoptosis. ATM-3507 significantly prolonged vinorelbine-induced mitotic arrest with elevated activity of the spindle assembly checkpoint and mitotic cell death; however, ATM-3507 showed minor impact on paclitaxel-induced mitotic defects. Both combinations substantially increased post-mitotic G1 arrest with cyclin D1 and E1 downregulation and an increase of p21Cip and p27Kip. CONCLUSION: Combined targeting of Tpm3.1/actin and microtubules is a promising treatment strategy for ovarian cancer that should be further tested in clinical settings.
Assuntos
Carcinoma Epitelial do Ovário/metabolismo , Cloretos/farmacologia , Neoplasias Ovarianas/metabolismo , Paclitaxel/farmacologia , Tropomiosina/metabolismo , Regulação para Cima , Vinorelbina/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário/tratamento farmacológico , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Tropomiosina/antagonistas & inibidores , Regulação para Cima/efeitos dos fármacosRESUMO
TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.
Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Imuno-Histoquímica , Mutação , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Ovarianas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Austrália , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Císticas, Mucinosas e Serosas/mortalidade , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Císticas, Mucinosas e Serosas/terapia , América do Norte , Variações Dependentes do Observador , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Análise Serial de Tecidos , Reino UnidoRESUMO
Alcohol consumption is correlated positively with risk for breast cancer in observational studies, but observational studies are subject to reverse causation and confounding. The association with epithelial ovarian cancer (EOC) is unclear. We performed both observational Cox regression and two-sample Mendelian randomization (MR) analyses using data from various European cohort studies (observational) and publicly available cancer consortia (MR). These estimates were compared to World Cancer Research Fund (WCRF) findings. In our observational analyses, the multivariable-adjusted hazard ratios (HR) for a one standard drink/day increase was 1.06 (95% confidence interval [CI]; 1.04, 1.08) for breast cancer and 1.00 (0.92, 1.08) for EOC, both of which were consistent with previous WCRF findings. MR ORs per genetically predicted one standard drink/day increase estimated via 34 SNPs using MR-PRESSO were 1.00 (0.93, 1.08) for breast cancer and 0.95 (0.85, 1.06) for EOC. Stratification by EOC subtype or estrogen receptor status in breast cancers made no meaningful difference to the results. For breast cancer, the CIs for the genetically derived estimates include the point-estimate from observational studies so are not inconsistent with a small increase in risk. Our data provide additional evidence that alcohol intake is unlikely to have anything other than a very small effect on risk of EOC.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Neoplasias da Mama/epidemiologia , Carcinoma Epitelial do Ovário/epidemiologia , Neoplasias Ovarianas/epidemiologia , Causalidade , Estudos de Coortes , Feminino , Humanos , Análise da Randomização Mendeliana , Razão de ChancesRESUMO
Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.
Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Biomarcadores Tumorais/análise , Queratina-7/análise , Proteínas de Ligação à Região de Interação com a Matriz/análise , Neoplasias Ovarianas/diagnóstico , Fatores de Transcrição/análise , Neoplasias do Apêndice/diagnóstico , Neoplasias do Apêndice/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Metástase Neoplásica/diagnóstico , Sensibilidade e EspecificidadeRESUMO
PURPOSE: Ovarian carcinomas are a group of distinct diseases classified by histotypes. As histotype-specific treatment evolves, accurate classification will become critical for optimal precision medicine approaches. EXPERIMENTAL DESIGN: To uncover differences between the two most common histotypes, high-grade serous (HGSC) and endometrioid carcinoma, we performed label-free quantitative proteomics on freshly frozen tumor tissues (HGSC, n = 10; endometrioid carcinoma, n = 10). Eight candidate protein biomarkers specific to endometrioid carcinoma were validated by IHC using tissue microarrays representing 361 cases of either endometrioid carcinoma or HGSC. RESULTS: More than 500 proteins were differentially expressed (P < 0.05) between endometrioid carcinoma and HGSC tumor proteomes. A ranked set of 106 proteins was sufficient to correctly discriminate 90% of samples. IHC validated KIAA1324 as the most discriminatory novel biomarker for endometrioid carcinoma. An 8-marker panel was found to exhibit superior performance for discriminating endometrioid carcinoma from HGSC compared with the current standard of WT1 plus TP53 alone, improving the classification rate for HGSC from 90.7% to 99.2%. Endometrioid carcinoma-specific diagnostic markers such as PLCB1, KIAA1324, and SCGB2A1 were also significantly associated with favorable prognosis within endometrioid carcinoma suggesting biological heterogeneity within this histotype. Pathway analysis of proteomic data revealed differences between endometrioid carcinoma and HGSC pertaining to estrogen and interferon signalling. CONCLUSIONS: In summary, these findings support the use of multi-marker panels for the differential diagnosis of difficult cases resembling endometrioid carcinoma and HGSC.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/classificação , Cistadenocarcinoma Seroso/classificação , Neoplasias Ovarianas/classificação , Proteoma/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , Proteoma/análise , Curva ROCRESUMO
DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
Assuntos
Carcinoma Epitelial do Ovário/genética , Metilação de DNA , Neoplasias Ovarianas/genética , População Branca/genética , Biomarcadores Tumorais/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Modelos Genéticos , Valor Preditivo dos Testes , Risco , Saúde da MulherRESUMO
BACKGROUND: Certain cultural, folk, and religious beliefs that are more common among African Americans (AAs) have been associated with later-stage breast cancer. It is unknown if these beliefs are similarly associated with delays in diagnosis of ovarian cancer. METHODS: Data from a multicenter case-control study of ovarian cancer in AA women were used to examine associations between cultural/folk beliefs and religious practices and stage at diagnosis and symptom duration before diagnosis. Associations between cultural/folk beliefs or religious practices and stage at diagnosis were assessed with logistic regression analyses, and associations with symptom duration with linear regression analyses. RESULTS: Agreement with several of the cultural/folk belief statements was high (e.g., 40% agreed that "if a person prays about cancer, God will heal it without medical treatments"), and â¼90% of women expressed moderate to high levels of religiosity/spirituality. Higher levels of religiosity/spirituality were associated with a twofold increase in the odds of stage III-IV ovarian cancer, whereas agreement with the cultural/folk belief statements was not associated with stage. Symptom duration before diagnosis was not consistently associated with cultural/folk beliefs or religiosity/spirituality. CONCLUSIONS: Women who reported stronger religious beliefs or practices had increased odds of higher stage ovarian cancer. Inaccurate cultural/folk beliefs about cancer treament were not associated with stage; however, these beliefs were highly prevalent in our population and could impact patient treatment decisions. Our findings suggest opportunities for health education interventions, especially working with churches, and improved doctor-patient communication.
Assuntos
Atitude Frente a Saúde/etnologia , Negro ou Afro-Americano/psicologia , Neoplasias Ovarianas/diagnóstico , Adulto , Idoso , Carcinoma Epitelial do Ovário/diagnóstico , Estudos de Casos e Controles , Feminino , Folclore , Humanos , Pessoa de Meia-Idade , Religião , Inquéritos e Questionários , Tempo para o Tratamento , Adulto JovemRESUMO
BACKGROUND: Black women with ovarian cancer in the U.S. have lower survival than whites. We aimed to identify factors associated with racial differences in ovarian cancer treatment and overall survival (OS). METHODS: We examined data from 365 white and 95 black ovarian cancer patients from the Hollings Cancer Center Cancer Registry in Charleston, S.C. between 2000 and 2015. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between race and receipt of surgery and chemotherapy, and Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs between race and OS. Model variables included diagnosis center, stage, histology, insurance status, smoking, age-adjusted Charlson comorbidity index (AACI) and residual disease. Interactions between race and AACI were assessed using -2 log likelihood tests. RESULTS: Blacks vs. whites were over two-fold less likely to receive a surgery-chemotherapy sequence (multivariable-adjusted OR 2.46, 95% CI 1.43-4.21), particularly if they had a higher AACI (interaction p = 0.008). In multivariable-adjusted Cox models, black women were at higher risk of death (HR 1.81, 95% CI 1.35-2.43) than whites, even when restricted to patients who received a surgery-chemotherapy sequence (HR 1.79, 95% CI 1.10-2.89) and particularly for those with higher AACI (HR 4.70, 95% CI 2.00 - 11.02, interaction p = 0.01). CONCLUSIONS: Among blacks, higher comorbidity associates with less chance of receiving guideline-based treatment and also modifies OS. Differences in receipt of guideline-based care do not completely explain survival differences between blacks and whites with ovarian cancer. These results highlight opportunities for further research.
Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Disparidades em Assistência à Saúde , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/terapia , População Branca/estatística & dados numéricos , Terapia Combinada , Comorbidade , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Prognóstico , Taxa de SobrevidaRESUMO
Identification of cancer patient subgroups using high throughput genomic data is of critical importance to clinicians and scientists because it can offer opportunities for more personalized treatment and overlapping treatments of cancers. In spite of tremendous efforts, this problem still remains challenging because of low reproducibility and instability of identified cancer subgroups and molecular features. In order to address this challenge, we developed Integrative Genomics Robust iDentification of cancer subgroups (InGRiD), a statistical approach that integrates information from biological pathway databases with high-throughput genomic data to improve the robustness for identification and interpretation of molecularly-defined subgroups of cancer patients. We applied InGRiD to the gene expression data of high-grade serous ovarian cancer from The Cancer Genome Atlas and the Australian Ovarian Cancer Study. The results indicate clear benefits of the pathway-level approaches over the gene-level approaches. In addition, using the proposed InGRiD framework, we also investigate and address the issue of gene sharing among pathways, which often occurs in practice, to further facilitate biological interpretation of key molecular features associated with cancer progression. The R package "InGRiD" implementing the proposed approach is currently available in our research group GitHub webpage ( https://dongjunchung.github.io/INGRID/ ).
Assuntos
Bases de Dados Factuais , Neoplasias Ovarianas/genética , Algoritmos , Austrália , Feminino , Genômica , Humanos , Análise de SobrevidaRESUMO
AIMS: Ovarian endometrioid carcinoma (EC) generally has a good prognosis. Adjuvant chemotherapy can be spared in low-stage disease, but prognostic biomarkers are needed to refine the treatment threshold. Wnt/ß-catenin signalling is commonly altered in EC. We examined immunohistochemical expression of nuclear ß-catenin and CDX2 as prognostic biomarkers for EC; both are mediators of the Wnt pathway. METHODS AND RESULTS: We evaluated two ovarian EC cohorts, discovery set (n = 183) and validation set (n = 174), with ovarian cancer-specific survival (OCSS) as the primary end-point. In univariable analysis, nuclear ß-catenin expression was significantly associated with longer OCSS in the discovery set [hazard ratio (HR) = 0.36, 95% confidence interval (CI) = 0.16-0.74, P = 0.004] and the validation set (HR = 0.35, 95% CI = 0.11-0.89, P = 0.006). Similar significant associations were observed with CDX2 expression in the discovery set (HR = 0.25, 95% CI = 0.11-0.50, P < 0.001) and validation set (HR = 0.27, 95% CI = 0.07-0.75, P = 0.020). In multivariable analysis, combined positivity of both markers was significantly associated with longer OCSS in the discovery set (HR = 0.20, 95% CI = 0.06-0.49, P < 0.001) and in the validation set (HR = 0.33 95% CI = 0.07-0.1.06, P = 0.047). In a stratified analysis for stage IC/II EC, combined positivity identified a subset of patients with a significantly longer OCSS in the discovery cohort but only a non-significant trend in the validation cohort. CONCLUSIONS: Nuclear ß-catenin and CDX2 expression individually or in combination are validated prognostic markers for ovarian EC. However, their full potential to stratify low risk patients at adjuvant threshold awaits further multimarker study.
Assuntos
Biomarcadores Tumorais/análise , Fator de Transcrição CDX2/biossíntese , Carcinoma Endometrioide/patologia , Neoplasias Ovarianas/patologia , beta Catenina/biossíntese , Adulto , Idoso , Carcinoma Endometrioide/mortalidade , Núcleo Celular/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
Primary mucinous carcinoma of the ovary is uncommon, and while numerous studies have focused on improving our ability to distinguish these tumors from gastrointestinal metastases, recent data suggest that up to one fifth are still misdiagnosed with a previously underrecognized culprit: endometrioid carcinoma. Using an index case of an ovarian endometrioid carcinoma with mucinous differentiation masquerading as a mucinous carcinoma, we sought to identify the most efficient biomarker combination that could distinguish these 2 histotypes. Eight immunohistochemical markers were assessed on tissue microarrays from 183 endometrioid carcinomas, 77 mucinous carcinomas, and 72 mucinous borderline tumors. Recursive partitioning revealed a simple 2-marker panel consisting of PR and vimentin. The combination of PR absence and vimentin absence could predict mucinous tumors with a sensitivity of 95.1%, a specificity of 96.7%, and an overall accuracy of 96.0%. Additional marker combinations did not improve accuracy. The 5-yr ovarian cancer-specific survival for mucinous carcinoma was significantly worse than endometrioid carcinoma (70% vs. 86%, respectively, P=0.02). Our proposed 2-marker algorithm allows diagnostic distinction between mucinous and endometrioid ovarian carcinomas when morphology is not straightforward. Given key differences in the underlying biology and clinical behavior of these 2 histotypes, improved diagnostic precision is essential for guiding appropriate management and treatment.
Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/diagnóstico , Neoplasias Ovarianas/diagnóstico , Vimentina/metabolismo , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Idoso , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Estudos de Coortes , Erros de Diagnóstico , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/patologia , Ovário/cirurgia , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Ovarian Clear Cell Carcinoma (OCCC) displays distinctive clinical and molecular characteristics and confers the worst prognosis among all ovarian carcinoma histotypes when diagnosed at advanced stage, because of the lack of effective therapy. IGF2BP3 is an RNA binding protein that modulates gene expression by post-transcriptional action. In this study, we investigated the roles of IGF2BP3 in the progression of OCCC. We used 328 OCCCs from the AOVT (the Alberta Ovarian Tumor Type study) and the COEUR (the Canadian Ovarian Experimental Unified Resource) cohorts to elucidate the associations between IGF2BP3 expression and clinicopathological parameters, with positive IGF2BP3 expression defined as diffuse block staining, being more frequently observed at stage III (P = 0.0056) and significantly associated with unfavorable overall survival (HR = 1.59, 95% CI 1.09-2.33) in multivariate analysis. IGF2BP3 mRNA gene expression was markedly increased in OCCC cell lines compared to normal tissues such as ovarian surface epithelium. We chose two IGF2BP3-overexpressing cell lines ES2 and OVMANA for in vitro and in vivo knockdown experiments. The proliferation and viability of both cell lines were significantly inhibited by two IGF2BP3 siRNAs and similar suppression was observed in cell migration and invasion by Wound Healing and Transwell assays. The percentage of apoptotic cancer cells was enhanced by both IGF2BP3 siRNAs. In vivo experiments showed significantly reduced sizes of tumors when treated with IGF2BP3 siRNA compared to controls. Furthermore, cancer metastasis-indicators MMP2 and MMP9 proteins were down-regulated. In conclusion, our study shows that IGF2BP3 expression is a promising biomarker for prognostication of women diagnosed with OCCC with multiple effects on key cell functions, supporting its role as an important cellular regulator with potential oncogenic activity, and as a potential target for future intervention strategies.
RESUMO
Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97â»1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03â»1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Assuntos
Adenocarcinoma Mucinoso/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , RNA Antissenso/genética , Timidilato Sintase/genética , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Hidroliases , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteínas/metabolismo , Locos de Características Quantitativas , RNA Antissenso/metabolismo , Risco , Transdução de Sinais , Timidilato Sintase/metabolismoRESUMO
OBJECTIVE: Major changes in the classification of ovarian carcinoma histotypes occurred over the last two decades, resulting in the current 2014 World Health Organization (WHO) diagnostic criteria that recognize five principal histotypes: high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous carcinoma. We assessed the impact of these guidelines and use of immunohistochemical (IHC) markers on classification of ovarian carcinomas in existing population-based studies. METHODS: We evaluated histotype classification for 2361 ovarian carcinomas diagnosed between 1999 and 2009 from two case-control studies using three approaches: 1. pre-2014 WHO ("historic") histotype; 2. Standardized review of pathology slides using the 2014 WHO criteria alone; and 3. An integrated IHC assessment along with the 2014 WHO criteria. We used Kappa statistics to assess agreement between approaches, and Kaplan-Meier survival curves and Cox proportional hazards models to evaluate mortality. RESULTS: Compared to the standardized pathologic review histotype, agreement across approaches was high (kappaâ¯=â¯0.892 for historic, and 0.849 for IHC integrated histotype), but the IHC integrated histotype identified more low-grade serous carcinomas and a subset of endometrioid carcinomas that were assigned as high-grade serous (nâ¯=â¯25). No substantial differences in histotype-specific mortality were observed across approaches. CONCLUSIONS: Our findings suggest that histotype assignment is fairly consistent regardless of classification approach, but that progressive improvements in classification accuracy for some less common histotypes are achieved with pathologic review using the 2014 WHO criteria and with IHC integration. We additionally recommend a classification scheme to fit historic data into the 2014 WHO categories to answer histotype-specific research questions.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma/patologia , Neoplasias Ovarianas/patologia , Ovário/patologia , Organização Mundial da Saúde , Adulto , Idoso , Carcinoma/classificação , Carcinoma/diagnóstico , Carcinoma/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Guias de Prática Clínica como AssuntoRESUMO
We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
Assuntos
Adenocarcinoma Mucinoso/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Neoplasias Ovarianas/metabolismo , Ovário/metabolismo , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/patologia , Prognóstico , Taxa de SobrevidaRESUMO
Although infrequently encountered, the diagnosis of ovarian high-grade endometrioid carcinoma remains a diagnostic challenge with potential consequences for targeted therapies and genetic counselling. We studied the clinical, morphologic, and immunohistochemical features of ovarian high-grade endometrioid carcinomas and their diagnostic reproducibility compared with tuboovarian high-grade serous carcinomas. Thirty cases confirmed as International Federation of Gynecology and Obstetrics grade 3 endometrioid carcinomas were identified from 182 ovarian endometrioid carcinomas diagnosed in Alberta, Canada, between 1978 and 2010, from the population-based Alberta Ovarian Tumor Types cohort. Cases of lower grade endometrioid and high-grade serous carcinoma served for comparison. Ten immunohistochemical markers were assessed on tissue microarrays. Clinical data were abstracted and survival analyses performed using Cox regression. Interobserver reproducibility for histologic type was assessed using 1 representative hematoxylin and eosin-stained slide from 25 randomly selected grade 3 endometrioid carcinomas and 25 high-grade serous carcinomas. Histotype was independently assigned by 5 pathologists initially blinded to immunohistochemical WT1/p53 status, with subsequent reassessment unblinded to WT1/p53 status. Patients diagnosed with grade 3 endometrioid carcinoma had a significantly longer survival compared with high-grade serous carcinoma in univariate analysis (hazard ratio [HR]=0.34, 95% confidence interval [CI]=0.16-0.67, P=0.0012) but not after adjusting for age, stage, treatment center, and residual tumor (HR=1.01, 95% CI=0.43-2.16, P=0.98). Grade 3 endometrioid carcinoma cases (N=30) were identical to grade 2 endometrioid carcinoma cases (N=23) with respect to survival in univariate analysis (HR=1.07, 95% CI=0.39-3.21, P=0.89) and immunohistochemical profile. Using histomorphology alone, interobserver agreement for the diagnosis of grade 3 endometrioid or high-grade serous carcinoma was 69%, which significantly increased (P<0.0001) to 96% agreement with the knowledge of WT1/p53 status. Our data support the diagnostic value of WT1/p53 status in differentiating between grade 3 endometrioid carcinoma and high-grade serous carcinoma. However, grade 3 and grade 2 endometrioid carcinomas showed no differences in immunophenotype or clinical parameters, suggesting that they could be combined into a single group.
Assuntos
Carcinoma Endometrioide/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alberta/epidemiologia , Biomarcadores Tumorais/análise , Carcinoma Endometrioide/química , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/terapia , Feminino , Humanos , Imuno-Histoquímica , Incidência , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/química , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/terapia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Tempo , Análise Serial de Tecidos , Resultado do Tratamento , Proteína Supressora de Tumor p53/análise , Proteínas WT1/análiseRESUMO
The aldehyde dehydrogenase 2 (ALDH2) polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol consumption and rs671 and ovarian cancer (OvCa) in Asians. We conducted a pooled analysis of Asian ancestry participants in the Ovarian Cancer Association Consortium. We included seven case-control studies and one cohort study comprising 460 invasive OvCa cases, 37 borderline mucinous OvCa and 1274 controls of Asian descent with information on recent alcohol consumption. Pooled odds ratios (OR) with 95% confidence intervals (CI) for OvCa risk associated with alcohol consumption, rs671 and their interaction were estimated using logistic regression models adjusted for potential confounders. No significant association was observed for daily alcohol intake with invasive OvCa (OR comparing any consumption to none = 0.83; 95% CI = 0.58-1.18) or with individual histotypes. A significant decreased risk was seen for carriers of one or both Lys alleles of rs671 for invasive mucinous OvCa (OR = 0.44; 95% CI = 0.20-0.97) and for invasive and borderline mucinous tumors combined (OR = 0.48; 95% CI = 0.26-0.89). No significant interaction was observed between alcohol consumption and rs671 genotypes. In conclusion, self-reported alcohol consumption at the quantities estimated was not associated with OvCa risk among Asians. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype. This association will require replication in a larger sample.
Assuntos
Adenocarcinoma Mucinoso/genética , Consumo de Bebidas Alcoólicas/genética , Aldeído-Desidrogenase Mitocondrial/genética , Povo Asiático/genética , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Estudos de Coortes , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Razão de ChancesRESUMO
With recent ovarian cancer screening studies showing no clinically significant mortality benefit, preventing this disease, identifying high-risk populations, and extending survival remain priorities. However, several challenges are impeding progress in ovarian cancer research. With most studies capturing exposure information from 10 or more years ago, evaluation of how changing patterns of exposures, such as new oral contraceptive formulations and increased intrauterine device use, might influence ovarian cancer risk and survival is difficult. Risk factors for ovarian cancer should be evaluated in the context of tumor histotypes, which have unique molecular features and cells of origin; this is a task that requires large collaborative studies to achieve meaningful sample sizes. Importantly, identification of novel modifiable risk factors, in addition to those currently known to reduce risk (eg, childbearing, tubal ligation, oral contraceptive use), is needed; this is not feasibly implemented at a population level. In this Commentary, we describe important gaps in knowledge and propose new approaches to advance epidemiologic research to improve ovarian cancer prevention and survival, including updated classification of tumors, collection of data on changing and novel exposures, longer follow-up on existing studies, evaluation of diverse populations, development of better risk prediction models, and collaborating prospectively with consortia to develop protocols for new studies that will allow seamless integration for future pooled analyses.
Assuntos
Projetos de Pesquisa Epidemiológica , Necessidades e Demandas de Serviços de Saúde , Neoplasias Ovarianas/epidemiologia , Viés , Anticoncepcionais Orais/uso terapêutico , Estudos Epidemiológicos , Feminino , Humanos , Fatores de RiscoRESUMO
Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes.Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival.Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470-3. ©2017 AACR.