Associations between plasma levels of brominated flame retardants and methylation of DNA from peripheral blood: A cross-sectional study in a cohort of French women.

BACKGROUND: Brominated flame retardants (BFRs) are organic compounds that are widespread in the environment. Because of their persistence, they are able to bioaccumulate with major impacts on human health. It has been hypothesized that the effect of BFRs on human health is mediated by alterations of DNA methylation. OBJECTIVE: The aim of this study was to examine the association between methylation of DNA extracted from peripheral blood and circulating levels of BFRs measured in plasma. METHODS: We conducted a methylation wide association study on 336 blood samples from a study within the E3N (Etude Epidémiologique auprès de femmes de l'Education Nationale) cohort, a long-term longitudinal cohort of French women. DNA methylation at more than 850 000 cytosine-guanine dinucleotide (CpG) sites was measured with the Illumina Infinium HumanMethylation - EPIC BeadChip. Circulating levels of seven BFRs (BDE-28, BDE-47, BDE-99, BDE-100, BDE-153, BDE-154 and PBB-153) were measured by gas chromatography coupled to high-resolution mass spectrometry in plasma samples. The association between DNA methylation and BFRs plasma levels was assessed through linear mixed-effects models followed by gene-set enrichment analyses (GSEA). RESULTS: We identified 253 CpG sites whose methylation levels were significantly associated with exposure to BFRs after Bonferroni correction. For 50 of these CpGs the p-values were less than 2.2x10-9 with the strongest association being between BDE-154 and cg23619365 (4.32x10-13). GSEA of CpG sites associated with exposure to BFRs identified significant enrichment of genes involved in hypoxia, glycolysis and adipogenesis. CONCLUSIONS: Exposure to BFRs appears to be related to numerous alterations in DNA methylation. These findings, if replicated in independent studies, provide insights into the biological and health effects of BFRs.

Plasma concentration of brominated flame retardants and postmenopausal breast cancer risk: a nested case-control study in the French E3N cohort.

BACKGROUND: Brominated flame retardants (BFRs) are lipophilic substances with endocrine-disrupting properties. To date, only few investigations, mainly retrospective case-control studies, have explored the link between internal levels of BFRs and the risk of breast cancer, leading to conflicting results. We investigated the associations between plasma concentrations of two main groups of BFRs, PBDEs (pentabromodiphenyl ethers) and PBBs (polybrominated biphenyls), and the risk of breast cancer in a nested case-control study. METHODS: A total of 197 incident breast cancer cases and 197 controls with a blood sample collected in 1994-1999 were included. Plasma levels of PBDE congeners (BDE-28, BDE-47, BDE-99, BDE-100, BDE153, BDE-154) and of PBB-153 were measured by gas chromatography coupled to high-resolution mass spectrometry. Conditional logistic regression models, adjusted for potential confounders, were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Women were aged 56 years on average at blood draw. All cases, except for one, were diagnosed after menopause, with an average age at diagnosis of 68 years. Overall, we found no evidence of an association between plasma levels of PBDEs and PBB-153 and postmenopausal breast cancer risk (log-concentrations of BFRs yielding non-statistically significant ORs of 0.87 to 1.07). The analysis showed a non-linear inverse association for BDE-100 and BDE-153 and postmenopausal breast cancer risk; nevertheless, these findings were statistically significant only when the exposure was modeled as ng/L plasma (third vs. first quintile: OR = 0.42, 95%CI = 0.19-0.93 and OR = 0.42, 95%CI = 0.18-0.98, respectively) and not when modeled as ng/gr of lipids (OR = 0.58, 95%CI = 0.27-1.25 and OR = 0.53, 95%CI = 0.25-1.17). These results were unchanged in stratified analyses by tumor hormone receptor expression or body mass index. CONCLUSIONS: Our results suggest no clear association between internal levels of PBDEs and PBB-153 and the risk of breast cancer in postmenopausal women. However, these findings need to be carefully interpreted, taking into account limitations due to the limited number of women included in the study, the lack of information concerning genetic susceptibility of cases, and the unavailability of exposure assessment during critical windows of susceptibility for breast cancer. More studies are warranted to further investigate the relationships between PBDE and PBB exposure and breast cancer risk.

Stem cell replication, somatic mutations and role of randomness in the development of cancer.

An intense scientific debate has recently taken place relating to the "bad luck" hypothesis in cancer development, namely that intrinsic random, and therefore unavoidable, mutagenic events would have a predominant role in tumorigenesis. In this article we review the main contributions to this debate and explain the reasons why the claim that cancer is mostly explained by intrinsic random factors is unsupported by data and theoretical models. In support of this, we present an analysis showing that smoking-induced mutations are more predictive of cancer risk than the lifetime number of stem cell cellular divisions.

Mitochondrial DNA copy number variation, leukocyte telomere length, and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

BACKGROUND: Leukocyte telomere length (LTL) and mitochondrial genome (mtDNA) copy number and deletions have been proposed as risk markers for various cancer types, including breast cancer (BC). METHODS: To gain a more comprehensive picture on how these markers can modulate BC risk, alone or in conjunction, we performed simultaneous measurements of LTL and mtDNA copy number in up to 570 BC cases and 538 controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. As a first step, we measured LTL and mtDNA copy number in 96 individuals for which a blood sample had been collected twice with an interval of 15 years. RESULTS: According to the intraclass correlation (ICC), we found very good stability over the time period for both measurements, with ICCs of 0.63 for LTL and 0.60 for mtDNA copy number. In the analysis of the entire study sample, we observed that longer LTL was strongly associated with increased risk of BC (OR 2.71, 95% CI 1.58-4.65, p = 3.07 × 10- 4 for highest vs. lowest quartile; OR 3.20, 95% CI 1.57-6.55, p = 1.41 × 10- 3 as a continuous variable). We did not find any association between mtDNA copy number and BC risk; however, when considering only the functional copies, we observed an increased risk of developing estrogen receptor-positive BC (OR 2.47, 95% CI 1.05-5.80, p = 0.04 for highest vs. lowest quartile). CONCLUSIONS: We observed a very good correlation between the markers over a period of 15 years. We confirm a role of LTL in BC carcinogenesis and suggest an effect of mtDNA copy number on BC risk.

Mutational and epigenetic signatures in cancer tissue linked to environmental exposures and lifestyle.

PURPOSE OF REVIEW: In this article, we describe how recent advances in the study of mutational and epigenetic signatures in tumours provide new opportunities to understand the role of the environment and lifestyle in cancer development. RECENT FINDINGS: Cancer-related mutational events have been investigated for decades but only recently the wide availability of genomic sequences and epigenomic data from thousands of cancer genomes has made it possible to identify numerous distinct mutational and epigenetic signatures through the application of advanced mathematical models. Some of these signatures have been linked to endogenous factors such as defective DNA repair or the action of APOBEC cytidine deaminases and to exogenous factors such as tobacco smoke, ultraviolet light, aflatoxins, aristolochic acid and ionizing radiation. More recently, it has been shown that exposure to factors such as tobacco smoke may also leave marks in the DNA methylation profile of both normal and tumour tissue in target organs. SUMMARY: The analysis of mutational and epigenetic signatures is a novel and useful tool to study cancer. Their application to experimental studies and to studies with detailed data on environmental exposures and lifestyle is likely to improve our understanding of how the environment and lifestyle influence cancer development and its evolution.

Respiratory syncytial virus-related hospital stays in adults in France from 2012 to 2021: A national hospital database study.

BACKGROUND: Respiratory syncytial virus (RSV) causes lower respiratory tract infections (LRTI) that may lead to hospitalization or death. The present study aimed to assess the burden of RSV infections in hospitalized adults. METHODS: RSV-related hospitalizations were identified from the nationwide hospital claims database in France (PMSI) from 2012 to 2021 using ICD-10 codes J12.1, J20.5, J21.0 or B97.4, and outcomes assessment focused on 2016-2020. In-hospital outcomes included length of stay, need for intensive care (ICU) and in-hospital all-cause mortality. Post-discharge outcomes included 30-day readmission for decompensation, 90-day RSV-related readmission, and 30 and 60-day in-hospital mortality. RESULTS: A cumulated number of 17 483 RSV-related stays were identified representing a rate of 72.0 cases per million stays. The outcomes assessment included 12,987 patients: 55.8 % were females and the mean age was 74.1 ± 16.4 years, with 57 % ≥ 75 years. Most of patients (78.6 %) had at least one comorbidity, mainly chronic respiratory (56.3 %) and cardiovascular diseases (41.3 %), or diabetes (23.5 %). A co-infection was found in 22.4 %, primarily bacterial (12 %). The mean length of stay was 12.3 ± 13.1 days. Overall, 10.9 % were admitted to an ICU and in-hospital mortality was 7.3 %. In-hospital outcomes were higher in cases of co-infection. Among 12 033 patients alive at discharge from the index stay, 6.5 % were readmitted with RSV within 90 days, 8.1 % for decompensation within 30 days, and 5.6 % died within 60-day. CONCLUSION: This study demonstrated the high burden of RSV infections in older adults and those with chronic conditions, and the need for preventive strategies.

Computational tools to detect signatures of mutational processes in DNA from tumours: A review and empirical comparison of performance.

Mutational signatures refer to patterns in the occurrence of somatic mutations that might be uniquely ascribed to particular mutational process. Tumour mutation catalogues can reveal mutational signatures but are often consistent with the mutation spectra produced by a variety of mutagens. To date, after the analysis of tens of thousands of exomes and genomes from about 40 different cancer types, tens of mutational signatures characterized by a unique probability profile across the 96 trinucleotide-based mutation types have been identified, validated and catalogued. At the same time, several concurrent methods have been developed for either the quantification of the contribution of catalogued signatures in a given cancer sequence or the identification of new signatures from a sample of cancer sequences. A review of existing computational tools has been recently published to guide researchers and practitioners through their mutational signature analyses, but other tools have been introduced since its publication and, a systematic evaluation and comparison of the performance of such tools is still lacking. In order to fill this gap, we have carried out an empirical evaluation of the main packages available to date, using both real and simulated data. Among other results, our empirical study shows that the identification of signatures is more difficult for cancers characterized by multiple signatures each having a small contribution. This work suggests that detection methods based on probabilistic models, especially EMu and bayesNMF, have in general better performance than NMF-based methods.

Association of Selenoprotein and Selenium Pathway Genotypes with Risk of Colorectal Cancer and Interaction with Selenium Status.

Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. Illumina Goldengate assays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (PACT = 0.10; PACT significance threshold was P < 0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development.

Identifying and correcting epigenetics measurements for systematic sources of variation.

Background: Methylation measures quantified by microarray techniques can be affected by systematic variation due to the technical processing of samples, which may compromise the accuracy of the measurement process and contribute to bias the estimate of the association under investigation. The quantification of the contribution of the systematic source of variation is challenging in datasets characterized by hundreds of thousands of features.In this study, we introduce a method previously developed for the analysis of metabolomics data to evaluate the performance of existing normalizing techniques to correct for unwanted variation. Illumina Infinium HumanMethylation450K was used to acquire methylation levels in over 421,000 CpG sites for 902 study participants of a case-control study on breast cancer nested within the EPIC cohort. The principal component partial R-square (PC-PR2) analysis was used to identify and quantify the variability attributable to potential systematic sources of variation. Three correcting techniques, namely ComBat, surrogate variables analysis (SVA) and a linear regression model to compute residuals were applied. The impact of each correcting method on the association between smoking status and DNA methylation levels was evaluated, and results were compared with findings from a large meta-analysis. Results: A sizeable proportion of systematic variability due to variables expressing 'batch' and 'sample position' within 'chip' was identified, with values of the partial R2 statistics equal to 9.5 and 11.4% of total variation, respectively. After application of ComBat or the residuals' methods, the contribution was 1.3 and 0.2%, respectively. The SVA technique resulted in a reduced variability due to 'batch' (1.3%) and 'sample position' (0.6%), and in a diminished variability attributable to 'chip' within a batch (0.9%). After ComBat or the residuals' corrections, a larger number of significant sites (k = 600 and k = 427, respectively) were associated to smoking status than the SVA correction (k = 96). Conclusions: The three correction methods removed systematic variation in DNA methylation data, as assessed by the PC-PR2, which lent itself as a useful tool to explore variability in large dimension data. SVA produced more conservative findings than ComBat in the association between smoking and DNA methylation.