Taylor, Philip R.

Abstract Background Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors. Methods We collated summary association statistics from fatty acid and cancer genome-wide association studies (GWAS) and subjected the collated data to a comprehensive QC pipeline. We identified metadata errors through comparison of study-specific statistics to external reference data sets (the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants: (i) GWAS hits for fatty acids, (ii) GWAS hits for cancer and (iii) a 1000 genomes reference set. Results We collated summary data from 6 fatty acid and 54 cancer GWAS. Metadata errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (11.6%). After resolving metadata errors and analytical issues, we created a data set of 219 842 genetic associations with 90 cancer types, generated in analyses of 566 665 cancer cases and 1 622 374 controls. Conclusions In this large MR collaboration, 11.6% of included studies were affected by a substantial metadata error or analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of downstream MR analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats).

Abstract To investigate whether insulin-like growth factor (IGF)-1 and IGF-binding protein-3 (IGFBP-3) are prospectively associated with exocrine pancreatic cancer, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of 29,133 male Finnish smokers, aged 50–69 years. To avoid the potential influence of subclinical cancer on IGF-1 and IGFBP-3, all subjects in this study were alive without clinical evidence of cancer during their 5th year of the cohort follow-up. Four hundred randomly selected cohort controls and 93 incident pancreatic adenocarcinoma cases that occurred between their 5th follow-up year through 1997 (i.e., up to 12.7 years of follow-up) were included in this study. Concentrations of IGF-1 and IGFBP-3 were measured in serum samples obtained at baseline using ELISA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models, adjusted for confounders. Neither IGF-1, IGFBP-3, nor the IGF-1:IGFBP-3 molar ratio was significantly associated with pancreatic cancer: highest compared to lowest tertile, OR = 0.67, 95% CI 0.37–1.21, P trend = 0.17; OR = 0.70, 95% CI 0.38–1.27, P trend = 0.12; and OR = 0.85, 95% CI 0.50–1.46, P trend = 0.54, respectively. Our results do not support the hypothesis that serum IGF-1 and IGFBP-3 concentrations are associated with pancreatic cancer risk among male smokers. Further studies are necessary to evaluate these associations in other populations.

Abstract Background: Discovery of methylated DNA markers (MDM) of esophageal squamous cell carcinoma (ESCC) has sparked interest in assessing these markers in tissue. We evaluated MDMs in ESCC from three geographically and ethnically distinct populations, and explored the feasibility of assaying MDMs from DNA obtained by swallowed balloon devices. Methods: MDMs were assayed in ESCC and normal tissues obtained from the populations of United States, Iran, and China, and from exfoliative cytology specimens obtained by balloons in a Chinese population. Areas under the receiver operating curve (AUC) of MDMs discriminating ESCC from normal tissues were calculated. Random forest prediction models were built, trained on U.S. cases and controls, and calibrated to U.S.-only controls (model 1) and three-country controls (model 2). Statistical tests were used to assess the relationship between dysplasia and MDM levels in balloons. Results: Extracted DNA from 333 ESCC and 322 normal tissues was analyzed, in addition to archival DNA from 98 balloons. For ESCC, model 1 validated in Iranian and Chinese tissues with AUCs of 0.90 and 0.87, and model 2 yielded AUCs of 0.99, 0.96, and 0.94 in tissues from the United States, Iran, and China, respectively. In Chinese balloons, MDMs showed a statistically significant trend of increasing levels with increasing grades of dysplasia (P < 0.004). Conclusions: MDMs accurately discriminate ESCC from normal esophagus in tissues obtained from high- and low-incidence countries. Preliminary data suggest that levels of MDMs assayed in DNA from swallowed balloon devices increase with dysplasia grade. Larger studies are needed to validate these results. Impact: MDMs coupled with minimally invasive collection methods have the potential for worldwide application in ESCC screening.

Abstract This study represents a multiplex cytokine analysis of serum from a 10-month randomized, controlled trial of 238 subjects that investigated the effects of selenomethionine and/or celecoxib in subjects with mild or moderate esophageal squamous dysplasia. The original chemoprevention study found that, among those with mild dysplasia, selenomethionine treatment favorably altered dysplasia grade. The current analysis found that selenomethionine downregulated interleukin (IL)-2 by 9% (P = 0.04), whereas celecoxib downregulated IL-7 by 11% (P = 0.006) and upregulated IL-13 by 17% (P = 0.008). In addition, an increase in IL-7 tertile from baseline to t10 was significantly associated with an increase in dysplasia grade, both overall [odds ratio (OR), 1.47; P = 0.03] and among those with mild dysplasia at t0 (OR, 2.53; P = 0.001). An increase in IL-2 tertile from baseline to t10 was also nonsignificantly associated with worsening dysplasia for all participants (OR, 1.32; P = 0.098) and significantly associated with worsening dysplasia among those with mild dysplasia at baseline (OR, 2.0; P = 0.01). The association of increased IL-2 with worsening dysplasia remained significant in those on selenomethionine treatment who began the trial with mild dysplasia (OR, 2.52; P = 0.03). The current study shows that selenomethionine supplementation decreased serum IL-2 levels, whereas celecoxib treatment decreased IL-7 levels and increased IL-13 levels during a 10-month randomized chemoprevention trial. An increase in IL-2 or IL-7 was associated with increased severity of dysplasia over the course of the trial, especially in those who began the trial with mild dysplasia. The favorable effect of selenomethionine on esophageal dysplasia in the original trial may have been mediated in part by its effect in reducing the levels of IL-2. Cancer Prev Res; 3(7); 810–7. ©2010 AACR.

AbstractA randomized, double-blinded, placebo-controlled 2 × 2 factorial chemoprevention trial was conducted in Linxian, China to assess the effects of selenomethionine and celecoxib on the natural history of esophageal squamous dysplasia. Results from this study indicated that asymptomatic adults with mild dysplasia were more likely to show an improvement when treated with selenomethionine compared with placebo (P = 0.02). Prompted by this finding, we examined the molecular profiles associated with regression and progression of dysplastic lesions in normal mucosa from 29 individuals, a subset of the Linxian cohort, using the Affymetrix U133A chip. Twenty differentially expressed genes were associated with regression and 129 were associated with progression when we compared the change in gene expression over time. Genes associated with immune response (n = 15), cell cycle (n = 15), metabolism (n = 15), calcium transport or calcium ion activity (n = 10), regulation of transcription (n = 9), signal transduction (n = 7), cytoskeleton and microtubules (n = 5), nucleotide processing and biosynthesis (n = 4), G-coupled signaling (n = 4), and apoptosis (n = 3) were present in the list of 149 genes. Using the Expression Analysis Systematic Explorer pathway analysis program, only the immune response pathway was significantly overrepresented among these 149 genes. Individuals whose lesions regressed seemed to have higher expression of genes associated with immune stimulation, such as antigen presentation, survival of T cells, and T-cell activation (HLA-DRA, HLA-DPA1, HLA-DBQ1, CD58, and FCER1A). In contrast, individuals whose lesions progressed had higher expression of genes involved in immune suppression and inflammation (CNR2, NFATC4, NFRKB, MBP, INHBB, CMKLR1, CRP, ORMS, SERPINA7, and SERPINA1). These data suggest that local and systemic immune responses may influence the natural history of esophageal squamous dysplasia. (Cancer Res 2006; 66(13): 6851-60)

Abstract Selenium is a promising cancer chemoprevention agent. A recent randomized controlled chemoprevention trial found that selenomethionine (SeMet) supplementation for 10 months favorably effected a change in esophageal dysplasia grade among participants who started the trial with mild dysplasia. To further explore the role of SeMet in this trial, we compared gene expression profiles by treatment group using Affymetrix HU 133A chips in before/after supplementation paired normal esophageal biopsies from a subset of 29 trial participants, 16 who received SeMet, and 13 who received placebo. Using P < 0.001 as a cutoff, 11 differentially expressed genes were found in the SeMet supplementation group but these genes did not include either known selenoprotein genes or genes previously shown to be modulated by selenium treatment. Because the number of differentially expressed genes (n = 11) was less than expected by chance (n = 18), we concluded that SeMet supplementation had no measurable effect on gene expression in the normal squamous esophagus of these subjects with dysplasia. (Cancer Epidemiol Biomarkers Prev 2006;15(5):1046-7)