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1.
Eur J Epidemiol ; 35(11): 1025-1042, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32959149

RESUMO

While childbearing protects against risk of epithelial ovarian cancer (EOC), few studies have explored the impact on maternal EOC risk of sex of offspring, which may affect the maternal environment during pregnancy. We performed a pooled analysis among parous participants from 12 case-controls studies comprising 6872 EOC patients and 9101 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression for case-control associations and polytomous logistic regression for histotype-specific associations, all adjusted for potential confounders. In general, no associations were found between offspring sex and EOC risk. However, compared to bearing only female offspring, bearing one or more male offspring was associated with increased risk of mucinous EOC (OR = 1.45; 95% CI = 1.01-2.07), which appeared to be limited to women reporting menarche before age 13 compared to later menarche (OR = 1.71 vs 0.99; P-interaction = 0.02). Bearing increasing numbers of male offspring was associated with greater risks of mucinous tumors (OR = 1.31, 1.84, 2.31, for 1, 2 and 3 or more male offspring, respectively; trend-p = 0.005). Stratifying by hormonally-associated conditions suggested that compared to bearing all female offspring, bearing a male offspring was associated with lower risk of endometrioid cancer among women with a history of adult acne, hirsutism, or polycystic ovary syndrome (OR = 0.49, 95% CI = 0.28-0.83) but with higher risk among women without any of those conditions (OR = 1.64 95% CI = 1.14-2.34; P-interaction = 0.003). Offspring sex influences the childbearing-EOC risk relationship for specific histotypes and conditions. These findings support the differing etiologic origins of EOC histotypes and highlight the importance of EOC histotype-specific epidemiologic studies. These findings also suggest the need to better understand how pregnancy affects EOC risk.

2.
JAMA Oncol ; 6(6): e200421, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32239218

RESUMO

Importance: Breastfeeding has been associated with a reduced risk of epithelial ovarian cancer in multiple studies, but others showed no association. Whether risk reduction extends beyond that provided by pregnancy alone or differs by histotype is unclear. Furthermore, the observed associations between duration and timing of breastfeeding with ovarian cancer risk have been inconsistent. Objective: To determine the association between breastfeeding (ie, ever/never, duration, timing) and ovarian cancer risk overall and by histotype. Design, Setting, and Participants: A pooled analysis of parous women with ovarian cancer and controls from 13 case-control studies participating in the Ovarian Cancer Association Consortium was performed. Odds ratios (ORs) and 95% CIs of the overall association were calculated using multivariable logistic regression and polytomous logistic regression for histotype-specific associations. All data were collected from individual sites from November 1989 to December 2009, and analysis took place from September 2017 to July 2019. Exposures: Data on breastfeeding history, including duration per child breastfed, age at first and last breastfeeding, and years since last breastfeeding were collected by questionnaire or interview and was harmonized across studies. Main Outcomes and Measures: Diagnosis of epithelial ovarian cancer. Results: A total of 9973 women with ovarian cancer (mean [SD] age, 57.4 [11.1] years) and 13 843 controls (mean [SD] age, 56.4 [11.7] years) were included. Breastfeeding was associated with a 24% lower risk of invasive ovarian cancer (odds ratio [OR], 0.76; 95% CI, 0.71-0.80). Independent of parity, ever having breastfed was associated with reduction in risk of all invasive ovarian cancers, particularly high-grade serous and endometrioid cancers. For a single breastfeeding episode, mean breastfeeding duration of 1 to 3 months was associated with 18% lower risk (OR, 0.82; 95% CI, 0.76-0.88), and breastfeeding for 12 or more months was associated with a 34% lower risk (OR, 0.66; 95% CI, 0.58-0.75). More recent breastfeeding was associated with a reduction in risk (OR, 0.56; 95% CI, 0.47-0.66 for <10 years) that persisted for decades (OR, 0.83; 95% CI, 0.77-0.90 for ≥30 years; P for trend = .02). Conclusions and Relevance: Breastfeeding is associated with a significant decrease in risk of ovarian cancer overall and for the high-grade serous subtype, the most lethal type of ovarian cancer. The findings suggest that breastfeeding is a potentially modifiable factor that may lower risk of ovarian cancer independent of pregnancy alone.

3.
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.


Assuntos
Adenocarcinoma de Células Claras/epidemiologia , Adenocarcinoma Mucinoso/epidemiologia , Carcinoma Endometrioide/epidemiologia , Neoplasias Ovarianas/epidemiologia , Síndrome do Ovário Policístico/epidemiologia , Feminino , Humanos , Análise da Randomização Mendeliana , Neoplasias Císticas, Mucinosas e Serosas/epidemiologia , Síndrome do Ovário Policístico/genética
4.
Cancer Epidemiol Biomarkers Prev ; 28(5): 996-999, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30967418

RESUMO

BACKGROUND: Relatively little is known about factors associated with long-term survival (LTS) following a diagnosis of ovarian cancer. METHODS: We conducted a retrospective study of high-grade serous ovarian cancer (HGSOC) to explore predictors of LTS (defined as ≥7 years of survival) using electronic medical record data from a network of integrated health care systems. Multivariable logistic regression with forward selection was used to compare characteristics of women who survived ≥7 years after diagnosis (n = 148) to those who died within 7 years of diagnosis (n = 494). RESULTS: Our final model included study site, age, stage at diagnosis, CA-125, comorbidity score, receipt of chemotherapy, BMI, and four separate comorbid conditions: weight loss, depression, hypothyroidism, and liver disease. Of these, only younger age, lower stage, and depression were statistically significantly associated with LTS. CONCLUSIONS: We did not identify any new characteristics associated with HGSOC survival. IMPACT: Prognosis of ovarian cancer generally remains poor. Large, pooled studies of ovarian cancer are needed to identify characteristics that may improve survival.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Cistadenocarcinoma Seroso/mortalidade , Neoplasias Ovarianas/mortalidade , Adolescente , Adulto , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , California/epidemiologia , Colorado/epidemiologia , Comorbidade , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Washington/epidemiologia , Adulto Jovem
5.
Gynecol Oncol ; 153(2): 343-355, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30898391

RESUMO

OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7). CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.


Assuntos
Carcinoma Epitelial do Ovário/genética , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
6.
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
8.
Int J Cancer ; 142(3): 460-469, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28833087

RESUMO

Menstrual pain, a common gynecological condition, has been associated with increased risk of ovarian cancer in some, but not all studies. Furthermore, potential variations in the association between menstrual pain and ovarian cancer by histologic subtype have not been adequately evaluated due to lack of power. We assessed menstrual pain using either direct questions about having experienced menstrual pain, or indirect questions about menstrual pain as indication for use of hormones or medications. We used multivariate logistic regression to calculate the odds ratio (OR) for the association between severe menstrual pain and ovarian cancer, adjusting for potential confounders and multinomial logistic regression to calculate ORs for specific histologic subtypes. We observed no association between ovarian cancer and menstrual pain assessed by indirect questions. Among studies using direct question, severe pain was associated with a small but significant increase in overall risk of ovarian cancer (OR = 1.07, 95% CI: 1.01-1.13), after adjusting for endometriosis and other potential confounders. The association appeared to be more relevant for clear cell (OR = 1.48, 95% CI: 1.10-1.99) and serous borderline (OR = 1.31, 95% CI: 1.05-1.63) subtypes. In this large international pooled analysis of case-control studies, we observed a small increase in risk of ovarian cancer for women reporting severe menstrual pain. While we observed an increased ovarian cancer risk with severe menstrual pain, the possibility of recall bias and undiagnosed endometriosis cannot be excluded. Future validation in prospective studies with detailed information on endometriosis is needed.


Assuntos
Dismenorreia/epidemiologia , Neoplasias Epiteliais e Glandulares/epidemiologia , Neoplasias Ovarianas/epidemiologia , Carcinoma Epitelial do Ovário , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Risco , Estados Unidos/epidemiologia
9.
Int J Epidemiol ; 47(2): 460-472, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29211900

RESUMO

Background: Ovarian cancer incidence differs substantially by race/ethnicity, but the reasons for this are not well understood. Data were pooled from the African American Cancer Epidemiology Study (AACES) and 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC) to examine racial/ethnic differences in epidemiological characteristics with suspected involvement in epithelial ovarian cancer (EOC) aetiology. Methods: We used multivariable logistic regression to estimate associations for 17 reproductive, hormonal and lifestyle characteristics and EOC risk by race/ethnicity among 10 924 women with invasive EOC (8918 Non-Hispanic Whites, 433 Hispanics, 911 Blacks, 662 Asian/Pacific Islanders) and 16 150 controls (13 619 Non-Hispanic Whites, 533 Hispanics, 1233 Blacks, 765 Asian/Pacific Islanders). Likelihood ratio tests were used to evaluate heterogeneity in the risk factor associations by race/ethnicity. Results: We observed statistically significant racial/ethnic heterogeneity for hysterectomy and EOC risk (P = 0.008), where the largest odds ratio (OR) was observed in Black women [OR = 1.64, 95% confidence interval (CI) = 1.34-2.02] compared with other racial/ethnic groups. Although not statistically significant, the associations for parity, first-degree family history of ovarian or breast cancer, and endometriosis varied by race/ethnicity. Asian/Pacific Islanders had the greatest magnitude of association for parity (≥3 births: OR = 0.38, 95% CI = 0.28-0.54), and Black women had the largest ORs for family history (OR = 1.77, 95% CI = 1.42-2.21) and endometriosis (OR = 2.42, 95% CI = 1.65-3.55). Conclusions: Although racial/ethnic heterogeneity was observed for hysterectomy, our findings support the validity of EOC risk factors across all racial/ethnic groups, and further suggest that any racial/ethnic population with a higher prevalence of a modifiable risk factor should be targeted to disseminate information about prevention.


Assuntos
Carcinoma Epitelial do Ovário/etnologia , Grupos Étnicos/estatística & dados numéricos , Neoplasias Ovarianas/etnologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Análise Multivariada , Paridade , Gravidez , Prevalência , Probabilidade , Fatores de Risco , Estados Unidos/epidemiologia , Adulto Jovem
10.
Cancer Epidemiol Biomarkers Prev ; 27(2): 174-182, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29141849

RESUMO

Background: Polycystic ovary syndrome (PCOS), and one of its distinguishing characteristics, oligomenorrhea, have both been associated with ovarian cancer risk in some but not all studies. However, these associations have been rarely examined by ovarian cancer histotypes, which may explain the lack of clear associations reported in previous studies.Methods: We analyzed data from 14 case-control studies including 16,594 women with invasive ovarian cancer (n = 13,719) or borderline ovarian disease (n = 2,875) and 17,718 controls. Adjusted study-specific ORs were calculated using logistic regression and combined using random-effects meta-analysis. Pooled histotype-specific ORs were calculated using polytomous logistic regression.Results: Women reporting menstrual cycle length >35 days had decreased risk of invasive ovarian cancer compared with women reporting cycle length ≤35 days [OR = 0.70; 95% confidence interval (CI) = 0.58-0.84]. Decreased risk of invasive ovarian cancer was also observed among women who reported irregular menstrual cycles compared with women with regular cycles (OR = 0.83; 95% CI = 0.76-0.89). No significant association was observed between self-reported PCOS and invasive ovarian cancer risk (OR = 0.87; 95% CI = 0.65-1.15). There was a decreased risk of all individual invasive histotypes for women with menstrual cycle length >35 days, but no association with serous borderline tumors (Pheterogeneity = 0.006). Similarly, we observed decreased risks of most invasive histotypes among women with irregular cycles, but an increased risk of borderline serous and mucinous tumors (Pheterogeneity < 0.0001).Conclusions: Our results suggest that menstrual cycle characteristics influence ovarian cancer risk differentially based on histotype.Impact: These results highlight the importance of examining ovarian cancer risk factors associations by histologic subtype. Cancer Epidemiol Biomarkers Prev; 27(2); 174-82. ©2017 AACR.


Assuntos
Ciclo Menstrual/fisiologia , Oligomenorreia/complicações , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/patologia , Síndrome do Ovário Policístico/complicações , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Oligomenorreia/fisiopatologia , Neoplasias Ovarianas/fisiopatologia , Síndrome do Ovário Policístico/fisiopatologia , Fatores de Risco , Autorrelato , Fatores de Tempo
11.
J Natl Cancer Inst ; 109(10)2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29117355

RESUMO

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 Risco
12.
Cancer Epidemiol Biomarkers Prev ; 26(9): 1470-1473, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28864456

RESUMO

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.


Assuntos
Neoplasias Ovarianas/mortalidade , Comorbidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Ovarianas/epidemiologia , Análise de Sobrevida
13.
Int J Cancer ; 140(11): 2422-2435, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28063166

RESUMO

Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival differs according to strata of ovarian cancer stage at diagnosis. In a large pooled analysis, we evaluated the association between various measures of cigarette smoking and survival among women with epithelial ovarian cancer. We obtained data from 19 case-control studies in the Ovarian Cancer Association Consortium (OCAC), including 9,114 women diagnosed with ovarian cancer. Cox regression models were used to estimate adjusted study-specific hazard ratios (HRs), which were combined into pooled hazard ratios (pHR) with corresponding 95% confidence intervals (CIs) under random effects models. Overall, 5,149 (57%) women died during a median follow-up period of 7.0 years. Among women diagnosed with ovarian cancer, both current (pHR = 1.17, 95% CI: 1.08-1.28) and former smokers (pHR = 1.10, 95% CI: 1.02-1.18) had worse survival compared with never smoking women. In histotype-stratified analyses, associations were observed for mucinous (current smoking: pHR = 1.91, 95% CI: 1.01-3.65) and serous histotypes (current smoking: pHR = 1.11, 95% CI: 1.00-1.23; former smoking: pHR = 1.12, 95% CI: 1.04-1.20). Further, our results suggested that current smoking has a greater impact on survival among women with localized than disseminated disease. The identification of cigarette smoking as a modifiable factor associated with survival has potential clinical importance as a focus area to improve ovarian cancer prognosis.


Assuntos
Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Fumar/efeitos adversos , Tabaco/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Adulto Jovem
14.
Am J Epidemiol ; 185(1): 8-20, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27941069

RESUMO

Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation.


Assuntos
Predisposição Genética para Doença , Neoplasias Ovarianas/etiologia , Doença Inflamatória Pélvica/complicações , História Reprodutiva , Carcinoma Epitelial do Ovário , Estudos de Casos e Controles , Comorbidade , Anticoncepcionais Orais Hormonais/administração & dosagem , Saúde da Família , Feminino , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Histerectomia , Neoplasias Epiteliais e Glandulares/epidemiologia , Neoplasias Epiteliais e Glandulares/etiologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Doença Inflamatória Pélvica/epidemiologia , Fatores de Proteção , Fatores de Risco , Esterilização Tubária , Talco/efeitos adversos
15.
Cancer Epidemiol Biomarkers Prev ; 26(1): 116-125, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28035019

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple loci associated with epithelial ovarian cancer (EOC) susceptibility, but further progress requires integration of epidemiology and biology to illuminate true risk loci below genome-wide significance levels (P < 5 × 10-8). Most risk SNPs lie within non-protein-encoding regions, and we hypothesize that long noncoding RNA (lncRNA) genes are enriched at EOC risk regions and represent biologically relevant functional targets. METHODS: Using imputed GWAS data from about 18,000 invasive EOC cases and 34,000 controls of European ancestry, the GENCODE (v19) lncRNA database was used to annotate SNPs from 13,442 lncRNAs for permutation-based enrichment analysis. Tumor expression quantitative trait locus (eQTL) analysis was performed for sub-genome-wide regions (1 × 10-5 > P > 5 × 10-8) overlapping lncRNAs. RESULTS: Of 5,294 EOC-associated SNPs (P < 1.0 × 10-5), 1,464 (28%) mapped within 53 unique lncRNAs and an additional 3,484 (66%) SNPs were correlated (r2 > 0.2) with SNPs within 115 lncRNAs. EOC-associated SNPs comprised 130 independent regions, of which 72 (55%) overlapped with lncRNAs, representing a significant enrichment (P = 5.0 × 10-4) that was more pronounced among a subset of 5,401 lncRNAs with active epigenetic regulation in normal ovarian tissue. EOC-associated lncRNAs and their putative promoters and transcription factors were enriched for biologically relevant pathways and eQTL analysis identified five novel putative risk regions with allele-specific effects on lncRNA gene expression. CONCLUSIONS: lncRNAs are significantly enriched at EOC risk regions, suggesting a mechanistic role for lncRNAs in driving predisposition to EOC. IMPACT: lncRNAs represent key candidates for integrative epidemiologic and functional studies. Further research on their biologic role in ovarian cancer is indicated. Cancer Epidemiol Biomarkers Prev; 26(1); 116-25. ©2016 AACR.


Assuntos
Predisposição Genética para Doença/epidemiologia , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Carcinoma Epitelial do Ovário , Estudos de Casos e Controles , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/epidemiologia , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Prevalência , Medição de Risco
16.
Oncotarget ; 7(43): 69097-69110, 2016 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-27533245

RESUMO

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.


Assuntos
Adenocarcinoma de Células Claras/genética , Predisposição Genética para Doença/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Adenocarcinoma de Células Claras/imunologia , Adulto , Idoso , Carcinoma Epitelial do Ovário , Feminino , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/imunologia , Neoplasias Ovarianas/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo II , Fatores de Risco , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
17.
Hum Mol Genet ; 25(16): 3600-3612, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27378695

RESUMO

Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 × 10 - 7). One of the most significant signals (Pall histologies = 1.01 × 10 - 13;Pserous = 3.54 × 10 - 14) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r2 = 0.90) with a previously identified 'best hit' (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 × 10 - 5 > P≥5.0 ×10 - 7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 - 5; PSKAT-o = 9.23 × 10 - 4) and KRT13 (PAML = 1.67 × 10 - 4; PSKAT-o = 1.07 × 10 - 5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.


Assuntos
Actinas/genética , Biotinidase/genética , Queratina-13/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Receptor Tipo 2 de Melanocortina/genética , Carcinoma Epitelial do Ovário , Exoma/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Proteínas de Neoplasias/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único
18.
Br J Cancer ; 115(1): 95-101, 2016 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-27299959

RESUMO

BACKGROUND: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality. METHODS: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years. RESULTS: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18-1.52) and without (HR=1.22, 95% CI: 1.12-1.33) further adjustment for residual disease, respectively. CONCLUSION: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.


Assuntos
Exercício Físico/fisiologia , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Recreação/fisiologia , Carcinoma Epitelial do Ovário , Feminino , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco
19.
Oncotarget ; 7(7): 7381-9, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26848776

RESUMO

BACKGROUND: Genome-wide association studies have identified several common susceptibility alleles for epithelial ovarian cancer (EOC). To further understand EOC susceptibility, we examined previously ungenotyped candidate variants, including uncommon variants and those residing within known susceptibility loci. RESULTS: At nine of eleven previously published EOC susceptibility regions (2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13), novel variants were identified that were more strongly associated with risk than previously reported variants. Beyond known susceptibility regions, no variants were found to be associated with EOC risk at genome-wide statistical significance (p <5x10(-8)), nor were any significant after Bonferroni correction for 17,000 variants (p< 3x10-6). METHODS: A customized genotyping array was used to assess over 17,000 variants in coding, non-coding, regulatory, and known susceptibility regions in 4,973 EOC cases and 5,640 controls from 13 independent studies. Susceptibility for EOC overall and for select histotypes was evaluated using logistic regression adjusted for age, study site, and population substructure. CONCLUSION: Given the novel variants identified within the 2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13 regions, larger follow-up genotyping studies, using imputation where necessary, are needed for fine-mapping and confirmation of low frequency variants that fall below statistical significance.


Assuntos
Biomarcadores Tumorais/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único/genética , Carcinoma Epitelial do Ovário , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Fatores de Risco
20.
Cancer Epidemiol ; 41: 71-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26851750

RESUMO

PURPOSE: Socioeconomic status (SES) is a known predictor of survival for several cancers and it has been suggested that SES differences affecting tumour stage at diagnosis may be the most important explanatory factor for this. However, only a limited number of studies have investigated SES differences in tumour stage at diagnosis of ovarian cancer. In a pooled analysis, we investigated whether SES as represented by level of education is predictive for advanced tumour stage at diagnosis of ovarian cancer, overall and by histotype. The effect of cigarette smoking and body mass index (BMI) on the association was also evaluated. METHODS: From 18 case-control studies, we obtained information on 10,601 women diagnosed with epithelial ovarian cancer. Study specific odds ratios (ORs) with corresponding 95% confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio (pOR) using a random effects model. RESULTS: Overall, women who completed ≤high school had an increased risk of advanced tumour stage at diagnosis compared with women who completed >high school (pOR 1.15; 95% CI 1.03-1.28). The risk estimates for the different histotypes of ovarian cancer resembled that observed for ovarian cancers combined but did not reach statistical significance. Our results were unchanged when we included BMI and cigarette smoking. CONCLUSION: Lower level of education was associated with an increased risk of advanced tumour stage at diagnosis of ovarian cancer. The observed socioeconomic difference in stage at diagnosis of ovarian cancer calls for further studies on how to reduce this diagnostic delay.


Assuntos
Neoplasias Epiteliais e Glandulares/epidemiologia , Neoplasias Ovarianas/epidemiologia , Classe Social , Idoso , Carcinoma Epitelial do Ovário , Estudos de Casos e Controles , Diagnóstico Tardio , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/patologia , Razão de Chances , Neoplasias Ovarianas/patologia
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