A multi-center population-based case–control study of ovarian cancer in African-American women: the African American Cancer Epidemiology Study (AACES)

Abstract: Background: Ovarian cancer (OVCA) is the leading cause of death from gynecological cancer, with poorer survival for African American (AA) women compared to whites. However, little is known about risk factors for OVCA in AA. To study the epidemiology of OVCA in this population, we started a collaborative effort in 10 sites in the US. Here we describe the study and highlight the challenges of conducting a study of a lethal disease in a minority population. Methods: The African American Cancer Epidemiology Study (AACES) is an ongoing, population-based case–control study of OVCA in AA in 10 geographic locations, aiming to recruit 850 women with invasive epithelial OVCA and 850 controls age- and geographically-matched to cases. Rapid case ascertainment and random-digit-dialing systems are in place to ascertain cases and controls, respectively. A telephone survey focuses on risk factors as well as factors of particular relevance for AAs. Food-frequency questionnaires, follow-up surveys, biospecimens and medical records are also obtained. Results: Current accrual of 403 AA OVCA cases and 639 controls exceeds that of any existing study to date. We observed a high proportion (15%) of deceased non-responders among the cases that in part is explained by advanced stage at diagnosis. A logistic regression model did not support that socio-economic status was a factor in advanced stage at diagnosis. Most risk factor associations were in the expected direction and magnitude. High BMI was associated with ovarian cancer risk, with multivariable adjusted ORs and 95% CIs of 1.50 (0.99-2.27) for obese and 1.27 (0.85- 1.91) for morbidly obese women compared to normal/underweight women. Conclusions: AACES targets a rare tumor in AAs and addresses issues most relevant to this population. The importance of the study is accentuated by the high proportion of OVCA cases ascertained as deceased. Our analyses indicated that obesity, highly prevalent in this population (>60% of the cases), was associated with increased OVCA risk. While these findings need to be replicated, they suggest the potential for an effective intervention on the risk in AAs. Upon completion of enrollment, AACES will be the largest epidemiologic study of OVCA in AA women

Primary peritoneal and ovarian cancers: an epidemiological comparative analysis

We performed case–control analyses using data from the North Carolina Ovarian Cancer Study to determine risk factors that distinguish primary peritoneal cancer (PPC) from epithelial ovarian cancer (EOC). Our risk factor analyses were restricted to invasive serous cancers including 495 EOC cases, 62 PPC cases and 1,086 control women. Logistic regression analyses were used to calculate adjusted odds ratios and 95% confidence intervals for risk factor associations. Although many case–control associations for the invasive serous PPC cases were similar to those of the invasive serous EOC cases, some differences were observed including a twofold increase in risk of invasive serous PPC in women who were ≥35 years at last pregnancy, whereas a decreased risk was observed for invasive serous EOC risk. We could not confirm a previous report of an association between tubal ligation and PPC, a factor consistently associated with a decreased risk of EOC. The difference in the risk factor associations between invasive serous PPC and EOC cancers suggests divergent molecular development of peritoneal and ovarian cancers. A larger study to determine risk factors for invasive serous PPC is warranted

Substrate Cooperativity in Marine Luciferases

Marine luciferases are increasingly used as reporters to study gene regulation. These luciferases have utility in bioluminescent assay development, although little has been reported on their catalytic properties in response to substrate concentration. Here, we report that the two marine luciferases from the copepods, Gaussia princeps (GLuc) and Metridia longa (MLuc) were found, surprisingly, to produce light in a cooperative manner with respect to their luciferin substrate concentration; as the substrate concentration was decreased 10 fold the rate of light production decreased 1000 fold. This positive cooperative effect is likely a result of allostery between the two proposed catalytic domains found in Gaussia and Metridia. In contrast, the marine luciferases from Renilla reniformis (RLuc) and Cypridina noctiluca (CLuc) demonstrate a linear relationship between the concentration of their respective luciferin and the rate of light produced. The consequences of these enzyme responses are discussed

The Association between Mediated Deprivation and Ovarian Cancer Survival among African American Women

BACKGROUND: Deprivation indices are often used to adjust for socio-economic disparities in health studies. Their role has been partially evaluated for certain population-level cancer outcomes, but examination of their role in ovarian cancer is limited. In this study, we evaluated a range of well-recognized deprivation indices in relation to cancer survival in a cohort of self-identified Black women diagnosed with ovarian cancer. This study aimed to determine if clinical or diagnostic characteristics lie on a mediating pathway between socioeconomic status (SES) and deprivation and ovarian cancer survival in a minority population that experiences worse survival from ovarian cancer. METHODS: We used mediation analysis to look at the direct and indirect causal effects of deprivation indices with main mediators of the SEER stage at diagnosis and residual disease. The analysis employed Bayesian structural equation models with variable selection. We applied a joint Bayesian structural model for the mediator, including a Weibull mixed model for the vital outcome with deprivation as exposure. We selected modifiers via a Monte Carlo model selection procedure. RESULTS: The results suggest that high SES-related indices, such as Yost, Kolak urbanicity (URB), mobility (MOB) and SES dimensions, and concentrated disadvantage index (CDI), all have a significant impact on improved survival. In contrast, area deprivation index (ADI)/Singh, and area level poverty (POV) did not have a major impact. In some cases, the indirect effects have very wide credible intervals, so the total effect is not well estimated despite the estimation of the direct effect. CONCLUSIONS: First, it is clear that commonly used indices such as Yost, or CDI both significantly impact the survival experience of Black women diagnosed with epithelial ovarian cancer. In addition, the Kolak dimension indices (URB, MOB, mixed immigrant: MICA and SES) also demonstrate a significant association, depending on the mediator. Mediation effects differ according to the mediator chosen

Association between DNA Damage Response and Repair Genes and Risk of Invasive Serous Ovarian Cancer

BACKGROUND: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study. METHODS/PRINCIPAL FINDINGS: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)(per allele) = 0.66; 95% credible interval (CI) = 0.44-1.00) and rs6005835 (median OR(per allele) = 0.69; 95% CI = 0.53-0.91) in CHEK2, rs2078486 (median OR(per allele) = 1.65; 95% CI = 1.21-2.25) and rs12951053 (median OR(per allele) = 1.65; 95% CI = 1.20-2.26) in TP53, rs411697 (median OR (rare homozygote) = 0.53; 95% CI = 0.35 - 0.79) in BACH1 and rs10131 (median OR( rare homozygote) = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. CONCLUSIONS/SIGNIFICANCE: Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results

Risk of Ovarian Cancer and Inherited Variants in Relapse-Associated Genes

Background: We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk. Methods and Findings: Women with and without invasive ovarian cancer (749 cases, 1,041 controls) were genotyped at 136 single nucleotide polymorphisms (SNPs) within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog) was associated with risk of serous cancer (p = 0.03); haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog) were associated with risk of invasive disease (p = 0.03). MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95 % CI 0.66–0.98; p = 0.03). SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p,0.05), and there was increased risk at HEXIM1 rs1053578 (p = 0.04, OR 1.40, 95 % CI 1.02–1.91). Conclusions: Tumor studies can reveal novel genes worthy of follow-up for cancer susceptibility. Here, we found that inherited markers in the gene encoding MSL1, part of a complex that modifies the histone H4, may decrease risk of invasiv

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study.

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

Polymorphisms in NF-κB Inhibitors and Risk of Epithelial Ovarian Cancer

<p>Abstract</p> <p>Background</p> <p>The nuclear factor-κB (NF-κB) family is a set of transcription factors with key roles in the induction of the inflammatory response and may be the link between inflammation and cancer development. This pathway has been shown to influence ovarian epithelial tissue repair. Inhibitors of κB (IκB) prevent NF-κB activation by sequestering NF-κB proteins in the cytoplasm until IκB proteins are phosphorylated and degraded.</p> <p>Methods</p> <p>We used a case-control study to evaluate the association between single nucleotide polymorphisms (SNPs) in <it>NFKBIA </it>and <it>NFKBIB </it>(the genes encoding IκBα and IκBβ, respectively) and risk of epithelial ovarian cancer. We queried 19 tagSNPs and putative-functional SNPs among 930 epithelial ovarian cancer cases and 1,037 controls from two studies.</p> <p>Results</p> <p>The minor allele for one synonymous SNP in <it>NFKBIA</it>, rs1957106, was associated with decreased risk (p = 0.03).</p> <p>Conclusion</p> <p>Considering the number of single-SNP tests performed and null gene-level results, we conclude that <it>NFKBIA </it>and <it>NFKBIB </it>are not likely to harbor ovarian cancer risk alleles. Due to its biological significance in ovarian cancer, additional genes encoding NF-κB subunits, activating and inhibiting molecules, and signaling molecules warrant interrogation.</p