Meat, fish, and ovarian cancer risk: Results from 2 Australian case-control studies, a systematic review, and meta-analysis

Background: Variation in meat and fish intakes has been associated with a risk of some cancers, but evidence for ovarian cancer is limited and inconsistent. Objective: We examined the association between intakes of total meat, red meat, processed meat, poultry, and fish and ovarian cancer risk. Design: Data came from 2 Australian population-based case-control studies conducted 10 y apart. Analyses included a total of 2049 cases and 2191 control subjects. We obtained dietary information via a food-frequency questionnaire. We estimated multivariable-adjusted odds ratios (ORs) for each study by using logistic regression and combined results of the 2 studies by using random-effects models. We also assembled the published evidence in a systematic review and meta-analysis. Results: Although there was no association between total or red meat intake and ovarian cancer risk, women with the highest intake of processed meat had a significantly increased risk of ovarian cancer in the 2 case-control studies (combined OR: 1.18; 95 CI: 1.15, 1.21) and the meta-analysis 7 studies; pooled relative risk (RR): 1.20; 95% CI: 1.07, 1.34. In contrast, a frequent intake of poultry was associated with borderline significant reductions in risk in the 2 case-control studies (combined OR: 0.83; 95% CI: 0.67, 1.03) and the meta-analysis including 7 additional studies (pooled RR: 0.90; 95% CI: 0.79, 1.01). High fish intake was associated with a significantly reduced risk in the 2 case-control studies (combined OR: 0.76; 95% CI: 0.62, 0.94) and a smaller borderline significant reduction in the meta-analysis (6 additional studies; pooled RR: 0.84; 95% CI: 0.68, 1.03). Conclusion: Our results suggest that low consumption of processed meat and higher consumption of poultry and fish may reduce the risk of ovarian cancer. © 2010 American Society for Nutrition

AD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Computing linkage disequilibrium aware genome embeddings using autoencoders

Motivation The completion of the genome has paved the way for genome-wide association studies (GWAS), which explained certain proportions of heritability. GWAS are not optimally suited to detect non-linear effects in disease risk, possibly hidden in non-additive interactions (epistasis). Alternative methods for epistasis detection using, e.g. deep neural networks (DNNs) are currently under active development. However, DNNs are constrained by finite computational resources, which can be rapidly depleted due to increasing complexity with the sheer size of the genome. Besides, the curse of dimensionality complicates the task of capturing meaningful genetic patterns for DNNs; therefore necessitates dimensionality reduction. Results We propose a method to compress single nucleotide polymorphism (SNP) data, while leveraging the linkage disequilibrium (LD) structure and preserving potential epistasis. This method involves clustering correlated SNPs into haplotype blocks and training per-block autoencoders to learn a compressed representation of the block’s genetic content. We provide an adjustable autoencoder design to accommodate diverse blocks and bypass extensive hyperparameter tuning. We applied this method to genotyping data from Project MinE, and achieved 99% average test reconstruction accuracy—i.e. minimal information loss—while compressing the input to nearly 10% of the original size. We demonstrate that haplotype-block based autoencoders outperform linear Principal Component Analysis (PCA) by approximately 3% chromosome-wide accuracy of reconstructed variants. To the extent of our knowledge, our approach is the first to simultaneously leverage haplotype structure and DNNs for dimensionality reduction of genetic data

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach

Dietary antioxidants and risk of Barrett's esophagus and adenocarcinoma of the esophagus in an Australian population

While dietary antioxidants are emerging as potentially modifiable risk factors for esophageal adenocarcinoma (EAC), studies on dietary antioxidants and its precursor Barrett's esophagus (BE) are limited. The present study extends previous work on BE by investigating risks of nondysplastic BE, dysplastic BE and EAC associated with intake of antioxidants such as vitamin C, vitamin E, β‐carotene, and selenium. Age and sex matched control subjects (n=577 for BE; n=1,507 for EAC) were sampled from an Australian population register. Information on demography, and well established EAC risk factors were obtained using self‐administered questionnaires. Intake of antioxidants for patients newly diagnosed with nondysplastic BE (n=266), dysplastic BE (n=101), or EAC (n=299), aged 18–79 years, were obtained using a food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable adjusted logistic regression models. High intake of β‐carotene from food and supplement sources combined was inversely associated with risk of dysplastic BE (OR Q4 vs. Q1=0.45; 95%CI: 0.20–1.00). High intake of vitamin E from food sources (OR Q4 vs. Q1=0.43; 95%CI: 0.28–0.67), from food and supplements combined (OR Q4 vs. Q1=0.64; 95%CI: 0.43–0.96), and a high antioxidant index score were inversely associated with risk of EAC. We found no significant trends between intake of β–carotene, vitamin C, vitamin E, and selenium and risk of nondysplastic or dysplastic BE. However, our data suggest that a high intake of β‐carotene may be associated with decreased risk of dysplastic BE.Torukiri I. Ibiebele, Maria Celia Hughes, Christina M. Nagle, Christopher J. Bain, David C. Whiteman, Penelope M. Webb for the Study of Digestive Health and Australian Cancer Stud

MelaNostrum: a consensus questionnaire of standardized epidemiologic and clinical variables for melanoma risk assessment by the melanostrum consortium

Background: Many melanoma observational studies have been carried out across different countries and geographic areas using heterogeneous assessments of epidemiologic risk factors and clinical variables. Aim: To develop a consensus questionnaire to standardize epidemiologic and clinical data collection for melanoma risk assessment. Methods: We used a stepwise strategy that included: compilation of variables from case–control datasets collected at various centres of the MelaNostrum Consortium; integration of variables from published case–control studies; consensus discussion of the collected items by MelaNostrum members; revision by independent experts; addition of online tools and image-based charts; questionnaire testing across centres and generation of a final draft. Results: We developed a core consensus questionnaire (MelanoQ) that includes four separate sections: A. general and demographic data; B. phenotypic and ultraviolet radiation exposure risk factors and lifestyle habits; C. clinical examination, medical and family history; and D. diagnostic data on melanoma (cases only). Accompanying online tools, informative tables, and image-based charts aid standardization. Different subsections of the questionnaire are designed for self-administration, patient interviews performed by a physician or study nurse, and data collection from medical records. Conclusions: The MelanoQ questionnaire is a useful tool for the collection and standardization of epidemiologic and clinical data across different studies, centres, cultures and languages. This will expedite ongoing efforts to compile high-quality data for pooled analyses or meta-analyses and offer a solid base for the design of clinical, epidemiologic and translational studies on melanoma. © 2018 European Academy of Dermatology and Venereolog