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1.
Int J Cancer ; 146(3): 739-748, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30963577

RESUMO

Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR≥0.4 ), and ≥15% NAA (AMR≥0.15 ), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10-4 ; 11p11.12, p = 7.0 × 10-4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR≥0.4 . In addition, we identified a peak at rs1620291 (p = 4.36 × 10-6 ) in 7q21.3. Among AMR≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10-4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10-4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies.


Assuntos
Afro-Americanos/genética , Predisposição Genética para Doença/genética , Glioma/etiologia , Glioma/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética/métodos , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Hispano-Americanos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Risco
2.
Am J Epidemiol ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31845738

RESUMO

In this issue of the American Journal of Epidemiology, Huang et al. report an inverse relationship between lifetime ovulatory cycle years (LOY) and circulating C-reactive protein (CRP), counter to their hypothesis. CRP is a non-specific systemic marker of chronic inflammation and there is evidence that there are other drivers of systemic inflammation as measured by CRP. There also is a body of evidence supporting that ovulation may be responsible for a localized inflammatory response. As ovarian cancer is the fifth most common cause of cancer death in women, preventive strategies are urgently needed. The findings of this report underscore the need for new research initiatives to determine the relationship between incessant ovulation and ovarian cancer risk in order to identify mechanisms of carcinogenesis that will lead to the prevention of this disease.

3.
Cancer ; 125(24): 4442-4451, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31415710

RESUMO

BACKGROUND: Discrimination and trust are known barriers to accessing health care. Despite well-documented racial disparities in the ovarian cancer care continuum, the role of these barriers has not been examined. This study evaluated the association of everyday discrimination and trust in physicians with a prolonged interval between symptom onset and ovarian cancer diagnosis (hereafter referred to as prolonged symptom duration). METHODS: Subjects included cases enrolled in the African American Cancer Epidemiology Study, a multisite case-control study of epithelial ovarian cancer among black women. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of everyday discrimination and trust in physicians with a prolonged symptom duration (1 or more symptoms lasting longer than the median symptom-specific duration), and it controlled for access-to-care covariates and potential confounders. RESULTS: Among the 486 cases in this analysis, 302 women had prolonged symptom duration. In the fully adjusted model, a 1-unit increase in the frequency of everyday discrimination increased the odds of prolonged symptom duration 74% (OR, 1.74; 95% CI, 1.22-2.49), but trust in physicians was not associated with prolonged symptom duration (OR, 0.86; 95% CI, 0.66-1.11). CONCLUSIONS: Perceived everyday discrimination was associated with prolonged symptom duration, whereas more commonly evaluated determinants of access to care and trust in physicians were not. These results suggest that more research on the effects of interpersonal barriers affecting ovarian cancer care is warranted.

4.
Int J Cancer ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31469419

RESUMO

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10-6 ), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3' of UGT2A2) and rs142091544 (5 kb 5' of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5' of follistatin [FST]), rs57403204 (81 kb 3' of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5' of PRPSAP1), rs116046250 (GABRG3 intronic) and rs192876988 (32 kb 3' of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow-up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (p = 0.002), increased risk of ER positive breast cancer in African ancestry women (p = 0.027) and decreased expression of GK2 in HGSOC tissue from African ancestry women (p = 0.004). A European ancestry-derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry.

5.
J Nutr ; 149(9): 1606-1616, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31152675

RESUMO

BACKGROUND: Chronic inflammation is associated with ovarian carcinogenesis; yet, the impact of inflammatory-related exposures on outcomes has been understudied. OBJECTIVE: Given the poor survival of women diagnosed with ovarian cancer, especially African-Americans, we examined whether diet-associated inflammation, a modifiable source of chronic systemic inflammation measured by the dietary inflammatory index (DII), was associated with all-cause mortality among African-American women with ovarian carcinoma. METHODS: Data were available from 490 ovarian carcinoma patients enrolled in a population-based case-control study of African-American women with ovarian cancer, the African-American Cancer Epidemiology Study. Energy-adjusted DII (E-DII) scores were calculated based on prediagnostic dietary intake of foods alone or foods and supplements, which was self-reported using the 2005 Block Food Frequency Questionnaire. Cox proportional hazards regression was used to estimate risk of mortality overall and for the most common histotype, high-grade serous carcinoma. Additionally, we assessed interaction by age at diagnosis and smoking status. RESULTS: Women included in this study had a median age of 57 y, and the majority of women were obese (58%), had late-stage disease (Stage III or IV, 66%), and had high-grade serous carcinoma (64%). Greater E-DII scores including supplements (indicating greater inflammatory potential) were associated with an increased risk of mortality among women with high-grade serous carcinoma (HR1-unit change: 1.08; 95% CI: 1.01, 1.17). Similar associations were observed for the E-DII excluding supplements, although not statistically significant (HR1-unit change: 1.07; 95% CI: 0.97, 1.17). There was an interaction by smoking status, where the positive association with mortality was present only among ever smokers (HRQuartile 4/Quartile 1: 2.36; 95% CI: 1.21, 4.60) but not among never smokers. CONCLUSIONS: Greater inflammatory potential of prediagnostic diet may adversely impact prognosis among African-American women with high-grade serous carcinoma, and specifically among ever smokers.

6.
Cancer Causes Control ; 30(9): 967-978, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31236792

RESUMO

PURPOSE: Although the incidence rate of epithelial ovarian cancer (EOC) is somewhat lower in African American (AA) than white women, survival is worse. The Ovarian Cancer in Women of African Ancestry (OCWAA) consortium will overcome small, study-specific sample sizes to better understand racial differences in EOC risk and outcomes. METHODS: We harmonized risk factors and prognostic characteristics from eight U.S. STUDIES: the North Carolina Ovarian Cancer Study (NCOCS), the Los Angeles County Ovarian Cancer Study (LACOCS), the African American Cancer Epidemiology Study (AACES), the Cook County Case-Control Study (CCCCS), the Black Women's Health Study (BWHS), the Women's Health Initiative (WHI), the Multiethnic Cohort Study (MEC), and the Southern Community Cohort Study (SCCS). RESULTS: Determinants of disparities for risk and survival in 1,146 AA EOC cases and 2,922 AA controls will be compared to 3,368 white EOC cases and 10,270 white controls. Analyses include estimation of population-attributable risk percent (PAR%) by race. CONCLUSION: OCWAA is uniquely positioned to study the epidemiology of EOC in AA women compared with white women to address disparities. Studies of EOC have been underpowered to address factors that may explain AA-white differences in the incidence and survival. OCWAA promises to provide novel insight into disparities in ovarian cancer.


Assuntos
Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/epidemiologia , Adulto , Afro-Americanos , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Illinois/epidemiologia , Incidência , Pessoa de Meia-Idade , North Carolina/epidemiologia , Fatores de Risco , Estados Unidos , Adulto Jovem
7.
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.

8.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1117-1126, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948450

RESUMO

BACKGROUND: Germline DNA copy number variation (CNV) is a ubiquitous source of genetic variation and remains largely unexplored in association with epithelial ovarian cancer (EOC) risk. METHODS: CNV was quantified in the DNA of approximately 3,500 cases and controls genotyped with the Illumina 610k and HumanOmni2.5M arrays. We performed a genome-wide association study of common (>1%) CNV regions (CNVRs) with EOC and high-grade serous (HGSOC) risk and, using The Cancer Genome Atlas (TCGA), performed in silico analyses of tumor-gene expression. RESULTS: Three CNVRs were associated (P < 0.01) with EOC risk: two large (∼100 kb) regions within the 610k set and one small (<5 kb) region with the higher resolution 2.5M data. Large CNVRs included a duplication at LILRA6 (OR = 2.57; P = 0.001) and a deletion at CYP2A7 (OR = 1.90; P = 0.007) that were strongly associated with HGSOC risk (OR = 3.02; P = 8.98 × 10-5). Somatic CYP2A7 alterations correlated with EGLN2 expression in tumors (P = 2.94 × 10-47). An intronic ERBB4/HER4 deletion was associated with reduced EOC risk (OR = 0.33; P = 9.5 × 10-2), and somatic deletions correlated with ERBB4 downregulation (P = 7.05 × 10-5). Five CNVRs were associated with HGSOC, including two reduced-risk deletions: one at 1p36.33 (OR = 0.28; P = 0.001) that correlated with lower CDKIIA expression in TCGA tumors (P = 2.7 × 10-7), and another at 8p21.2 (OR = 0.52; P = 0.002) that was present somatically where it correlated with lower GNRH1 expression (P = 5.9 × 10-5). CONCLUSIONS: Though CNV appears to not contribute largely to EOC susceptibility, a number of low-to-common frequency variants may influence the risk of EOC and tumor-gene expression. IMPACT: Further research on CNV and EOC susceptibility is warranted, particularly with CNVs estimated from high-density arrays.

9.
J Neurooncol ; 142(3): 479-487, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30796745

RESUMO

PURPOSE: Telomere length-associated SNPs have been associated with incidence and survival rates for malignant brain tumors such as glioma. Here, we study the influence of genetically determined lymphocyte telomere length (LTL) by comparing telomerase associated SNPs between the most common non-malignant brain tumor, i.e. meningioma, and healthy controls. METHODS/PATIENTS: One thousand fifty-three (1053) surgically treated meningioma patients and 4437 controls of Western European ancestry were included. Germline DNA was genotyped for 8 SNPs previously significantly associated with LTL. Genotypically-estimated LTL was then calculated by summing each SNP's genotypically-specified telomere length increase in base pairs (bp) for each person. Odds ratios for genotypically-estimated LTL in meningioma cases and controls were evaluated using logistic regression with the first two ancestral principal components and sex as covariates. RESULTS: Three out of the eight evaluated LTL SNPs were significantly associated with increased meningioma risk (rs10936599: OR 1.14, 95% CI 1.01-1.28, rs2736100: OR 1.13, 95% CI 1.03-1.25, rs9420907: OR 1.22, 95% CI 1.07-1.39). Only rs9420907 remained significant after correction for multiple testing. Average genotypically-estimated LTL was significantly longer for those with meningioma compared to controls [mean cases: 560.2 bp (standard error (SE): 4.05 bp), mean controls: 541.5 bp (SE: 2.02 bp), logistic regression p value = 2.13 × 10-5]. CONCLUSION: Increased genotypically-estimated LTL was significantly associated with increased meningioma risk. A role for telomere length in the pathophysiology of meningioma is novel, and could lead to new insights on the etiology of meningioma.


Assuntos
Leucócitos/patologia , Neoplasias Meníngeas/etiologia , Meningioma/etiologia , Polimorfismo de Nucleotídeo Único , Homeostase do Telômero , Estudos de Casos e Controles , Feminino , Seguimentos , Genótipo , Humanos , Leucócitos/metabolismo , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Prognóstico , Fatores de Risco
10.
Sci Rep ; 9(1): 309, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670737

RESUMO

Little is known about the causes of meningioma. Obesity and obesity-related traits have been reported in several epidemiological observational studies to be risk factors for meningioma. We performed an analysis of genetic variants associated with obesity-related traits to assess the relationship with meningioma risk using Mendelian randomization (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. We considered 11 obesity-related traits, identified genetic instruments for these factors, and assessed their association with meningioma risk using data from a genome-wide association study comprising 1,606 meningioma patients and 9,823 controls. To evaluate the causal relationship between the obesity-related traits and meningioma risk, we consider the estimated odds ratio (OR) of meningioma for each genetic instrument. We identified positive associations between body mass index (odds ratio [ORSD] = 1.27, 95% confidence interval [CI] = 1.03-1.56, P = 0.028) and body fat percentage (ORSD = 1.28, 95% CI = 1.01-1.63, P = 0.042) with meningioma risk, albeit non-significant after correction for multiple testing. Associations for basal metabolic rate, diastolic blood pressure, fasting glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, systolic blood pressure, total cholesterol, triglycerides and waist circumference with risk of meningioma were non-significant. Our analysis provides additional support for obesity being associated with an increased risk of meningioma.

11.
Int J Epidemiol ; 48(5): 1416-1424, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30597039

RESUMO

BACKGROUND: Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power. METHODS: We aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods. RESULTS: We found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97-1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94-1.07), P = 0.99] or ER- [1.02 (0.90-1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93-1.07), P = 0.99] or the advanced subtype [1.02 (0.90-1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy. CONCLUSIONS: Despite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency.

12.
J Natl Cancer Inst ; 111(1): 60-68, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29718305

RESUMO

Background: The understanding of ovarian cancer pathogenesis has recently shifted to recognize distinct changes in how ovarian cancer histotypes are defined. Using the 2014 World Health Organization (WHO) diagnostic guidelines, we classified ovarian cancer histotypes in Surveillance, Epidemiology, and End Results (SEER) cancer registry data and examined survival patterns by histotype and disease stage. Methods: We extracted data on 28 118 incident epithelial ovarian cancer cases diagnosed in 2004-2014 from SEER and defined histotype using the 2014 WHO guidelines (high-grade serous, low-grade serous, endometrioid, clear cell, mucinous, carcinosarcoma, and malignant Brenner tumors). By histotype and disease stage, we estimated Kaplan-Meier survival curves and calculated age-adjusted overall and cause-specific survival estimates. Cox proportional hazards regression models were used to estimate histotype-specific hazard ratios (HRs) and 95% confidence intervals (CIs) by disease stage while adjusting for age at diagnosis, region, race/ethnicity, and receipt of surgery. Results: Within two years after diagnosis, localized/regional-stage carcinosarcoma and distant-stage mucinous, clear cell, and carcinosarcoma had a higher risk of mortality compared with high-grade serous, with the most pronounced association for localized/regional carcinosarcoma (>1-2-year time period: HR = 3.81, 95% CI = 2.74 to 5.30) and distant-stage mucinous (0-1-year time period: HR = 3.87, 95% CI = 3.45 to 4.34). In the time period more than four to 10 years after diagnosis, hazard ratios for all histotypes relative to high-grade serous, irrespective of disease stage, were less than 1.00. Cumulatively, both localized/regional and distant-stage low-grade serous and endometrioid carcinomas had the most favorable outcomes. Conclusions: Our large study, which is representative of the United States population and incorporates the most current knowledge of ovarian cancer pathogenesis, highlights the need to recognize ovarian cancer as a set of distinct diseases and not a single entity. Only then will we be able to effectively target the unique features of each histotype to reduce ovarian cancer mortality.

13.
J Womens Health (Larchmt) ; 28(4): 444-451, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30481095

RESUMO

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 ∼90% 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.

14.
J Womens Health (Larchmt) ; 28(2): 284-293, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30307782

RESUMO

OBJECTIVE: While the incidence of epithelial ovarian cancer (EOC) is lower among African American (AA) women compared with European American (EA) women, AA women have markedly worse outcomes. In this study, we describe individual, social, and societal factors in health-related quality of life (HRQL) in AA women diagnosed with EOC in the African American Cancer Epidemiology Study (AACES) that we hypothesize may influence a patient's capacity to psychosocially adjust to a diagnosis of cancer. METHODS: There were 215 invasive EOC cases included in the analysis. HRQL was measured using the SF-8 component scores for physical (PCS) and mental (MCS) health. We used least squares regression to test the effects of individual dispositional factors (optimism and trait anxiety); social level (perceived social support); and societal-level factors (SES defined as low family income and low educational attainment, and perceived discrimination) on HRQL, while adjusting for patient age, tumor stage, body mass index, and comorbidity. Mediation analysis was applied to test whether social support and physical activity buffer impacts of EOC on HRQL. RESULTS: Optimism, trait anxiety, social support, poverty, and past perceived discrimination were significantly associated with HRQL following diagnosis of EOC. Specifically, higher family income, lower phobic anxiety, and higher social support were associated with better wellbeing on the MCS and PCS (p < 0.01). Higher perceived discrimination was associated with both lower MCS and PCS, whereas higher optimism was associated with higher MCS. Physical activity (MET-min/week) and social support displayed significant overall mediation for effects of SES on MCS and PCS, but not for trait anxiety. CONCLUSIONS: Both pre- and postdiagnosis characteristics of AA women with EOC are important predictors of HRQL after cancer diagnosis. Individual, social, and societal-level factors each contribute to HRQL status with EOC and should be assessed.

15.
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
16.
Cancer Epidemiol Biomarkers Prev ; 28(3): 555-562, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30482874

RESUMO

BACKGROUND: There have been few studies of sufficient size to address the relationship between glioma risk and the use of aspirin or NSAIDs, and results have been conflicting. The purpose of this study was to examine the associations between glioma and aspirin/NSAID use, and to aggregate these findings with prior published studies using meta-analysis. METHODS: The Glioma International Case-Control Study (GICC) consists of 4,533 glioma cases and 4,171 controls recruited from 2010 to 2013. Interviews were conducted using a standardized questionnaire to obtain information on aspirin/NSAID use. We examined history of regular use for ≥6 months and duration-response. Restricted maximum likelihood meta-regression models were used to aggregate site-specific estimates, and to combine GICC estimates with previously published studies. RESULTS: A history of daily aspirin use for ≥6 months was associated with a 38% lower glioma risk, compared with not having a history of daily use [adjusted meta-OR = 0.62; 95% confidence interval (CI), 0.54-0.70]. There was a significant duration-response trend (P = 1.67 × 10-17), with lower ORs for increasing duration of aspirin use. Duration-response trends were not observed for NSAID use. In the meta-analysis aggregating GICC data with five previous studies, there was a marginally significant association between use of aspirin and glioma (mOR = 0.84; 95% CI, 0.70-1.02), but no association for NSAID use. CONCLUSIONS: Our study suggests that aspirin may be associated with a reduced risk of glioma. IMPACT: These results imply that aspirin use may be associated with decreased glioma risk. Further research examining the association between aspirin use and glioma risk is warranted.

17.
Neuro Oncol ; 21(1): 71-82, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30124908

RESUMO

Background: To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods: Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10-6 and in the validation set when P < 0.001 in 2 of 3 algorithms. Results: Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. Conclusions: These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

18.
Int J Gynecol Pathol ; 38(2): 157-170, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29485423

RESUMO

African American women with high-grade serous ovarian carcinoma have worse outcomes compared with women of European descent. Although the discrepancy is partially attributed to differences in access to care, the tumor immune microenvironment may also contribute. Expression of targetable immune regulatory molecules such as programmed cell death ligand-1 (PD-L1) and indoleamine 2,3 dioxygenase (IDO) is of particular interest as it may help guide therapy in this population. Using cases from the largest study of African American women with ovarian cancer, the African American Cancer Epidemiology Study, we characterized PD-L1 and IDO expression in 112 high-grade serous ovarian carcinomas. Immunohistochemistry for PD-L1, IDO, CD8, FOX3p, and CD68 was performed. PD-L1 and IDO were scored as the percentage of positive tumor cells and tumor-associated immune cells. CD8 and FOX3p counts were averaged across 10 high-power fields. Cox proportional hazards regression was used to evaluate the association between PD-L1 and IDO expression and survival. Tumor cells were positive for PD-L1 and IDO in 29% and 58% of cases, respectively. The majority showed <10% staining, and no cases exceeded 25% positivity. The majority of PD-L1-positive cases coexpressed IDO. PD-L1 and IDO expression was associated with higher CD8 and FOX3p counts (P<0.05). No association was observed between PD-L1 and IDO and survival. In summary, expression of PD-L1 and IDO is seen in a subset of high-grade serous ovarian carcinoma from African American women and is correlated with elevated lymphocyte infiltration. While PD-L1 and IDO co-expression suggests a role for dual immunotherapy, diffuse expression of PD-L1 and IDO is rare, invoking caution regarding the potential for immunotherapeutic response.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Cistadenocarcinoma Seroso/diagnóstico , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias Ovarianas/diagnóstico , Afro-Americanos , Idoso , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/terapia , Feminino , Humanos , Imuno-Histoquímica , Imunoterapia , Linfócitos do Interstício Tumoral , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Prognóstico , Microambiente Tumoral
19.
Cancer Causes Control ; 29(11): 1081-1091, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30269307

RESUMO

BACKGROUND: The association between common benign gynecologic conditions and ovarian cancer remains under-studied in African Americans. Therefore, we examine the association between self-reported history of benign gynecologic conditions and epithelial ovarian cancer risk in African-American women. METHODS: Data from a large population-based, multi-center case-control study of epithelial ovarian cancer in African-American women were analyzed to estimate the association between self-reported history of endometriosis, pelvic inflammatory disease (PID), fibroid, and ovarian cyst with epithelial ovarian cancer. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the associations between individual and composite gynecologic conditions and ovarian cancer. RESULTS: 600 cases and 752 controls enrolled in the African American Cancer Epidemiology Study between 1 December 2010 and 31 December 2015 comprised the study population. After adjusting for potential confounders, a history of endometriosis was associated with ovarian cancer (OR 1.78; 95% CI 1.09-2.90). A non-significant association of similar magnitude was observed with PID (OR 1.33; 95% CI 0.82-2.16), while no association was observed in women with a history of fibroid or ovarian cyst. A positive trend was observed for an increasing number of reported gynecologic conditions (p = 0.006) with consistency across histologic subtypes and among both oral contraceptive users and non-users. CONCLUSION: A self-reported history of endometriosis among African-American women was associated with increased risk of ovarian cancer. Having multiple benign gynecologic conditions also increased ovarian cancer risk.


Assuntos
Afro-Americanos/estatística & dados numéricos , Carcinoma Epitelial do Ovário/epidemiologia , Doenças dos Genitais Femininos/epidemiologia , Neoplasias Ovarianas/epidemiologia , Adulto , Idoso , Carcinoma Epitelial do Ovário/etnologia , Estudos de Casos e Controles , Endometriose/epidemiologia , Feminino , Doenças dos Genitais Femininos/etnologia , Humanos , Leiomioma/epidemiologia , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Cistos Ovarianos/epidemiologia , Neoplasias Ovarianas/etnologia , Doença Inflamatória Pélvica/epidemiologia , Fatores de Risco , Neoplasias Uterinas/epidemiologia , Adulto Jovem
20.
J Pathol Clin Res ; 4(4): 250-261, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30062862

RESUMO

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 Sobrevida
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