Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 179
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Epidemiology ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32028322

RESUMO

BACKGROUND: Menopausal estrogen-alone therapy is a risk factor for endometrial and ovarian cancers. When a progestin is included with the estrogen daily (continuous estrogen-progestin combined therapy), there is no increased risk of endometrial cancer. However, the effect of continuous estrogen-progestin combined therapy on risk of ovarian cancer is less clear. METHODS: We pooled primary data from five population-based case-control studies in the Ovarian Cancer Association Consortium, including 1,509 postmenopausal ovarian cancer cases and 2,295 postmenopausal controls. Information on previous menopausal hormonal therapy use, as well as ovarian cancer risk factors, was collected using in-person interviews. Logistic regression was used to assess the association between use of continuous estrogen-progestin combined therapy and risk of ovarian cancer by duration and recency of use and disease histotype. RESULTS: Ever postmenopausal use of continuous estrogen-progestin combined therapy was not associated with increased risk of ovarian cancer overall (OR=0.85, 95% CI 0.72-1.0). A decreased risk was observed for mucinous ovarian cancer (OR=0.40, 95% CI 0.18-0.91). The other main ovarian cancer histotypes did not show an association (endometrioid: OR=0.86, 95% CI 0.57-1.3, clear cell: OR=0.68, 95% CI 0.40-1.2, serous: OR=0.98, 95% CI 0.80-1.2). CONCLUSIONS: Given that estrogen-alone therapy has been shown to be associated with increased risk of ovarian cancer, these findings are consistent with the hypothesis that adding a progestin each day ameliorates the carcinogenic effects of estrogen on the cells of origin for all histotypes of ovarian cancer.

2.
J Ovarian Res ; 12(1): 116, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771659

RESUMO

BACKGROUND: Cancer Antigen 125 (CA125) is currently the best available ovarian cancer screening biomarker. However, CA125 has been limited by low sensitivity and specificity in part due to normal variation between individuals. Personal characteristics that influence CA125 could be used to improve its performance as screening biomarker. METHODS: We developed and validated linear and dichotomous (≥35 U/mL) circulating CA125 prediction models in postmenopausal women without ovarian cancer who participated in one of five large population-based studies: Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n = 861), the Nurses' Health Studies (NHS/NHSII, n = 81), and the New England Case Control Study (NEC, n = 923). The prediction models were developed using stepwise regression in PLCO and validated in EPIC, NHS/NHSII and NEC. RESULT: The linear CA125 prediction model, which included age, race, body mass index (BMI), smoking status and duration, parity, hysterectomy, age at menopause, and duration of hormone therapy (HT), explained 5% of the total variance of CA125. The correlation between measured and predicted CA125 was comparable in PLCO testing dataset (r = 0.18) and external validation datasets (r = 0.14). The dichotomous CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, time since menopause, and duration of HT with AUC of 0.64 in PLCO and 0.80 in validation dataset. CONCLUSIONS: The linear prediction model explained a small portion of the total variability of CA125, suggesting the need to identify novel predictors of CA125. The dichotomous prediction model showed moderate discriminatory performance which validated well in independent dataset. Our dichotomous model could be valuable in identifying healthy women who may have elevated CA125 levels, which may contribute to reducing false positive tests using CA125 as screening biomarker.

3.
Cancer Epidemiol Biomarkers Prev ; 28(11): 1835-1844, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31455671

RESUMO

BACKGROUND: Douching is associated with disorders involving genital tract inflammation and genital talc use with epithelial ovarian cancer (EOC), but their joint effects are infrequently considered. METHODS: From 2,040 cases of EOC and 2,100 controls enrolled in eastern Massachusetts and New Hampshire, we used unconditional logistic regression to estimate risk for EOC associated with douching and/or talc use. In subsets of cases and controls, we also collected information about pelvic inflammatory disease (PID), ectopic pregnancy, and cervical neoplasia to estimate risk for these events from douching and/or talc use. RESULTS: The adjusted OR and 95% confidence interval (CI) for all EOC was 0.94 (0.76-1.16) in women who douched but never used talc and 1.28 (1.09-1.51) in women who used talc but never douched. Compared with women who never regularly douched or used talc, ORs (95% CIs) were 0.83 (0.52-1.33) for women who both used talc and homemade douches and 1.53 (1.11-2.10) for women who both used talc and store-bought douches. Cases who both douched and used talc were more likely to have had PID compared with cases who had used neither [OR = 5.03 (95% CI, 1.61-15.7)]. CONCLUSIONS: Douching is not an independent risk factor for ovarian cancer, but the combination of talc use and store-bought douches may modestly increase the risk for EOC beyond that for talc use alone. IMPACT: The joint effect of talc use and douching, especially with commercial products, should be considered in evaluating risks associated with disorders involving genital tract inflammation or EOC.

4.
Am J Clin Pathol ; 152(5): 590-607, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31305893

RESUMO

OBJECTIVES: Genital talc use is associated with increased risk for ovarian carcinoma in epidemiologic studies. Finding talc in pelvic tissues in women with ovarian carcinoma who have used talc is important in documenting exposure and assessing talc's biologic potential, but tissue-based morphology studies have been rarely reported. METHODS: We report five patient cases with documented perineal talc use, each of whom had talc (by both polarized light and scanning electron microscopy) in multiple pelvic sites distant from the perineum. Six negative-exposure control patients were also analyzed. RESULTS: Talc particles were found in exposed patients, typically within two or more of the following locations: pelvic region lymph nodes, cervix, uterine corpus, fallopian tubes, and ovaries. CONCLUSIONS: Our report adds new insights into the biologic potential of talc and suggests additional anatomic sites that should be closely examined for talc by oncologic surgical pathologists in the setting of perineal talc use.

5.
Int J Epidemiol ; 48(3): 822-830, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31211375

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer. METHODS: Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls). RESULTS: An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65-0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations. CONCLUSION: Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.

6.
Cancer Epidemiol Biomarkers Prev ; 28(6): 1076-1085, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30948451

RESUMO

BACKGROUND: Cancer antigen 125 (CA125) is the most promising ovarian cancer screening biomarker to date. Multiple studies reported CA125 levels vary by personal characteristics, which could inform personalized CA125 thresholds. However, this has not been well described in premenopausal women. METHODS: We evaluated predictors of CA125 levels among 815 premenopausal women from the New England Case Control Study (NEC). We developed linear and dichotomous (≥35 U/mL) CA125 prediction models and externally validated an abridged model restricting to available predictors among 473 premenopausal women in the European Prospective Investigation into Cancer and Nutrition Study (EPIC). RESULTS: The final linear CA125 prediction model included age, race, tubal ligation, endometriosis, menstrual phase at blood draw, and fibroids, which explained 7% of the total variance of CA125. The correlation between observed and predicted CA125 levels based on the abridged model (including age, race, and menstrual phase at blood draw) had similar correlation coefficients in NEC (r = 0.22) and in EPIC (r = 0.22). The dichotomous CA125 prediction model included age, tubal ligation, endometriosis, prior personal cancer diagnosis, family history of ovarian cancer, number of miscarriages, menstrual phase at blood draw, and smoking status with AUC of 0.83. The abridged dichotomous model (including age, number of miscarriages, menstrual phase at blood draw, and smoking status) showed similar AUCs in NEC (0.73) and in EPIC (0.78). CONCLUSIONS: We identified a combination of factors associated with CA125 levels in premenopausal women. IMPACT: Our model could be valuable in identifying healthy women likely to have elevated CA125 and consequently improve its specificity for ovarian cancer screening.

7.
Cancer Med ; 8(5): 2503-2513, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31001917

RESUMO

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

8.
Ultrastruct Pathol ; 43(1): 13-27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30898001

RESUMO

Perineal talc use is associated with ovarian carcinoma in many case-control studies. Such talc may migrate to pelvic organs and regional lymph nodes, with both clinical and legal significance. Our goal was to differentiate talc in pelvic lymph nodes due to exposure, versus contamination with talc in the laboratory. We studied 22 lymph nodes from ovarian tumor patients, some of which had documented talc exposure, to quantify talc using digestion of tissue taken from paraffin blocks and scanning electron microscopy/energy dispersive X-ray analysis (SEM/EDX). Talc particles correlated significantly with surface contamination assessments using polarized light microscopy. After adjusting for surface contamination, talc burdens in nodes correlated strongly with perineal talc use. In a separate group of lymph nodes, birefringent particles within the same plane of focus as the tissues in histological sections were highly correlated with talc particles within the tissue by in situ SEM/EDX (r = 0.80; p < 0.0001). We conclude that since talc can be a surface contaminant from tissue collection/preparation, digestion measurements may be influenced by contamination. Instead, because they preserve anatomic landmarks and permit identification of particles in cells and tissues, polarized light microscopy and in situ SEM/EDX are recommended to assess talc in lymph nodes.


Assuntos
Linfonodos/patologia , Microscopia Eletrônica de Varredura , Neoplasias Ovarianas/patologia , Estudos de Casos e Controles , Feminino , Humanos , Microscopia Eletrônica de Varredura/métodos , Microscopia de Polarização/métodos , Pelve/patologia
9.
Cancer Causes Control ; 30(5): 537-547, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30905014

RESUMO

PURPOSE: Previous epidemiologic studies have shown that smoking, obesity, and physical inactivity are associated with poor survival following a diagnosis of ovarian cancer. Yet, the combined relationship of these unfavorable lifestyle factors on ovarian cancer survival has not been sufficiently investigated. METHODS: Using data pooled from 13 studies, we examined the associations between combined exposures to smoking, overweight/obesity weight, and physical inactivity and overall survival (OS) as well as progression-free survival (PFS) among women diagnosed with invasive epithelial ovarian carcinoma (n = 7,022). Using age- and stage-adjusted Cox proportional hazards regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with joint exposure to these factors. RESULTS: Combined exposure to current smoking, overweight/obesity, and physical inactivity prior to diagnosis was associated with a significantly increased risk of mortality compared to women who never smoked, had normal body mass index (BMI), and were physically active (HR = 1.37; 95% CI 1.10-1.70). The association for a joint exposure to these factors exceeded that of each exposure individually. In fact, exposure to both current smoking and overweight/obesity, and current smoking and physical inactivity was also associated with increased risk of death (HR = 1.28; 95% CI 1.08-1.52, and HR = 1.26; 95% CI 1.04-1.54, respectively). The associations were of a similar magnitude when former smoking was assessed in combination with the other exposures and when excessive weight was limited to obesity only. No significant associations were observed between joint exposure to any of these factors and PFS. CONCLUSIONS: Joint exposure to smoking, excessive weight, and physical inactivity may negatively impact survival of ovarian cancer patients. These results suggest the importance of examining the combined effect of lifestyle factors on ovarian cancer patients' survival.


Assuntos
Carcinoma Epitelial do Ovário/epidemiologia , Neoplasias Ovarianas/epidemiologia , Comportamento Sedentário , Fumar/epidemiologia , Feminino , Humanos , Atividade Motora , Obesidade/complicações , Neoplasias Ovarianas/mortalidade , Sobrepeso/complicações , Modelos de Riscos Proporcionais , Fatores de Risco , Fumar/efeitos adversos , Ganho de Peso
10.
J Natl Cancer Inst ; 111(1): 5-6, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29718448
11.
Int J Cancer ; 144(9): 2192-2205, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30499236

RESUMO

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.


Assuntos
Exposição Ambiental/efeitos adversos , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/genética , Estudos de Casos e Controles , Anticoncepcionais Orais Hormonais , Meio Ambiente , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Risco
12.
Cancer Res ; 79(3): 505-517, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30559148

RESUMO

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 , Grupo com Ancestrais do Continente Europeu/genética , Neoplasias Ovarianas/genética , Biomarcadores Tumorais/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Modelos Genéticos , Valor Preditivo dos Testes , Risco , Saúde da Mulher
13.
Int J Cancer ; 144(5): 991-1000, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30006925

RESUMO

Statins are widely used to lower blood cholesterol and reduce risk for cardiovascular diseases, but attention has recently focused on a role in cancer prevention or therapy. Here we present data from a large case-control study addressing whether statin use can lower the risk for epithelial ovarian cancer (EOC). Between 1992 and 2008, data including medications used for at least 6 months were collected from 2,040 cases with EOC and 2,100 frequency-matched controls without the disease who participated in the New England Case Control study. We used unconditional logistic regression controlling for matching factors and potential confounders to examine the association between statin use and the risk for EOC. Overall, women who used statins had 32% lower risk of ovarian cancer compared to non-users (Odds ratio (OR) 0.68, 95% Confidence Interval (CI): 0.54-0.85), adjusting for the matching factors and other covariates. The reduced risk was most apparent in women taking a lipophilic statin who began use after age 49, and who had used them 2-4.9 years. Statin use was associated with lower risks for both serous and non-serous histologic subtypes with the strongest effect seen for mucinous and mixed epithelial subtypes. The association became apparent about a decade after the introduction of statins and did not appear to be confounded by indications for use of statins or medications used concomitantly. In this case-control study, statins were found to lower the risk for both serous and non-serous EOC and especially mucinous EOC.


Assuntos
Carcinoma Epitelial do Ovário/induzido quimicamente , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias Ovarianas/induzido quimicamente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , New England , Razão de Chances , Fatores de Risco
14.
Cancer Epidemiol Biomarkers Prev ; 27(12): 1483-1490, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30237250

RESUMO

BACKGROUND: Randomized trials using the biomarker cancer antigen (CA) 125, with or without pelvic ultrasound, have failed to show a clear benefit of general population screening for ovarian cancer. In part, this may be due to a lack of information about conditions, besides ovarian cancer, that can alter CA125 levels and affect specificity or sensitivity. We evaluated the association between common medical conditions and CA125 levels among women without ovarian cancer. METHODS: We used data and specimens from 2,004 women without ovarian cancer who participated in the New England Case Control study between 1992 and 2008. Participants completed in-person interviews and donated blood samples at enrollment. We measured CA125 using the CA125II assay and calculated the association between medical conditions and log-transformed CA125 using linear regression. RESULTS: The median age of participants was 53 years and 1,119 (56%) were postmenopausal. The average CA125 level was 14.5 units/mL for premenopausal and 11.7 for postmenopausal women. Among premenopausal women, CA125 was significantly lower for women with colon polyps (P = 0.06) and hysterectomy (P = 0.01) and significantly higher with endometriosis (P = 0.05). CA125 was also significantly higher in premenopausal women with coronary artery disease (CVD) (P < 0.01, n = 2 cases) but not among postmenopausal with CVD (n = 79). Furthermore, among postmenopausal women, CA125 was significantly lower for women with osteoporosis, hypercholesterolemia, and osteoarthritis (P = 0.03, 0.02, and 0.01 respectively) and higher for women with a history of inflammatory bowel disease (P = 0.04). CONCLUSIONS: Several chronic diseases are associated with CA125, which could influence the interpretation of CA125 in the context of ovarian cancer screening. IMPACT: Consideration of chronic medical conditions may be necessary to interpret CA125 values.


Assuntos
Antígeno Ca-125/sangue , Doença Crônica , Feminino , Humanos , Pessoa de Meia-Idade
15.
J Pathol ; 246(4): 459-469, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30229909

RESUMO

Mucinous ovarian tumors (MOTs) morphologically and epidemiologically resemble mucinous cystic neoplasms (MCNs) of the pancreas, sharing a similar stroma and both occurring disproportionately among young females. Additionally, MOTs and MCNs share similar clinical characteristics and immunohistochemical phenotypes. Exome sequencing has revealed frequent recurrent mutations in KRAS and RNF43 in both MOTs and MCNs. The cell of origin for these tumors remains unclear, but MOTs sometimes arise in the context of mature cystic teratomas and other primordial germ cell (PGC) tumors. We undertook the present study to investigate whether non-teratoma-associated MOTs and MCNs share a common cell of origin. Comparisons of the gene expression profiles of MOTs [including both the mucinous borderline ovarian tumors (MBOTs) and invasive mucinous ovarian carcinomas (MOCs)], high-grade serous ovarian carcinomas, ovarian surface epithelium, Fallopian tube epithelium, normal pancreatic tissue, pancreatic duct adenocarcinomas, MCNs, and single-cell RNA-sequencing of PGCs revealed that both MOTs and MCNs are more closely related to PGCs than to either eutopic epithelial tumors or normal epithelia. We hypothesize that MCNs may arise from PGCs that stopped in the dorsal pancreas during their descent to the gonads during early human embryogenesis, while MOTs arise from PGCs in the ovary. Together, these data suggest a common pathway for the development of MCNs and MOTs, and suggest that these tumors may be more properly classified as germ cell tumor variants. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Linhagem da Célula , Células Germinativas/patologia , Neoplasias Císticas, Mucinosas e Serosas/embriologia , Neoplasias Embrionárias de Células Germinativas/embriologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/embriologia , Neoplasias Pancreáticas/embriologia , Adulto , Biologia Computacional/métodos , Mineração de Dados/métodos , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Células Germinativas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Morfogênese , Neoplasias Císticas, Mucinosas e Serosas/classificação , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Císticas, Mucinosas e Serosas/metabolismo , Neoplasias Embrionárias de Células Germinativas/classificação , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fenótipo , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos
16.
Cancer Res ; 78(18): 5419-5430, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30054336

RESUMO

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.


Assuntos
Carcinoma Epitelial do Ovário/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Ovarianas/genética , Transcriptoma , Carcinogênese , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Prognóstico , Locos de Características Quantitativas , Fatores de Risco
17.
PLoS One ; 13(7): e0197561, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29979793

RESUMO

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.


Assuntos
Proteínas de Ancoragem à Quinase A/genética , Carcinoma Epitelial do Ovário/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Carcinoma Epitelial do Ovário/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Fatores de Risco
18.
Cancer Epidemiol Biomarkers Prev ; 27(7): 790-804, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29661801

RESUMO

Background: Neoplastic and non-neoplastic events may raise levels of mucins, CA15.3, and CA125, and generate antibodies against them, but their impact on epithelial ovarian cancer (EOC) risk has not been fully defined.Methods: CA15.3, CA125, and IgG1 antibodies against them were measured in 806 women who developed EOC and 1,927 matched controls from the European Prospective Investigation of Nutrition and Cancer. Associations between epidemiologic factors and anti-mucin antibodies were evaluated using generalized linear models; EOC risks associated with anti-mucin antibodies, by themselves or in combination with respective antigens, were evaluated using conditional logistic regression.Results: In controls, lower antibodies against both mucins were associated with current smoking; and, in postmenopausal women, higher levels with longer oral contraceptive use and later-age-at and shorter-interval-since last birth. Lower anti-CA15.3 antibodies were associated with higher body mass and, in premenopausal women, more ovulatory cycles. Higher anti-CA15.3 and anti-CA125 antibodies were associated with higher risk for mucinous EOC occurring ≥ 3 years from enrollment. Long-term risk for serous EOC was reduced in women with low CA125 and high anti-CA125 antibodies relative to women with low concentrations of both.Conclusions: We found general support for the hypothesis that anti-mucin antibody levels correlate with risk factors for EOC. Antibodies alone or in combinations with their antigen may predict longer term risk of specific EOC types.Impact: Anti-CA125 and anti-CA15.3 antibodies alone or in perspective of antigens may be informative in the pathogenesis of EOC subtypes, but less useful for informing risk for all EOC. Cancer Epidemiol Biomarkers Prev; 27(7); 790-804. ©2018 AACR.


Assuntos
Biomarcadores Tumorais/genética , Antígeno Ca-125/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Estudos Prospectivos , Fatores de Risco
20.
Int J Cancer ; 143(3): 515-526, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29473162

RESUMO

Immuno-proteomic screening has identified several tumor-associated autoantibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer-testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies. We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53 and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo-luminiscence. Diagnostic discrimination statistics were calculated by strata of lead-time between blood collection and diagnosis. With lead times ≤6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08-0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10-0.44] for P53 (0.33 [0.11-0.68] for high-grade serous tumors). However, at longer lead-times, the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01-0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited.


Assuntos
Antígenos de Neoplasias/imunologia , Autoanticorpos/imunologia , Detecção Precoce de Câncer , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/imunologia , Adulto , Idoso , Antígenos de Neoplasias/sangue , Biomarcadores Tumorais , Antígeno Ca-125 , Estudos de Casos e Controles , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Estudos Prospectivos , Fatores de Risco , Sensibilidade e Especificidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA