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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.

ObjectivesWe conducted a systematic literature review and meta-analysis of observational studies to investigate the association between diabetes, hypertension, body mass index (BMI) or smoking with the risk of death in patients with COVID-19 and to estimate the proportion of deaths attributable to these conditions.MethodsRelevant observational studies were identified by searches in the PubMed, Cochrane library and Embase databases through 14 November 2020. Random-effects models were used to estimate summary relative risks (SRRs) and 95% CIs. Certainty of evidence was assessed using the Cochrane methods and the Grading of Recommendations, Assessment, Development and Evaluations framework.ResultsA total of 186 studies representing 210 447 deaths among 1 304 587 patients with COVID-19 were included in this analysis. The SRR for death in patients with COVID-19 was 1.54 (95% CI 1.44 to 1.64, I2=92%, n=145, low certainty) for diabetes and 1.42 (95% CI 1.30 to 1.54, I2=90%, n=127, low certainty) for hypertension compared with patients without each of these comorbidities. Regarding obesity, the SSR was 1.45 (95% CI 1.31 to 1.61, I2=91%, n=54, high certainty) for patients with BMI ≥30 kg/m2 compared with those with BMI <30 kg/m2 and 1.12 (95% CI 1.07 to 1.17, I2=68%, n=25) per 5 kg/m2 increase in BMI. There was evidence of a J-shaped non-linear dose–response relationship between BMI and mortality from COVID-19, with the nadir of the curve at a BMI of around 22–24, and a 1.5–2-fold increase in COVID-19 mortality with extreme obesity (BMI of 40–45). The SRR was 1.28 (95% CI 1.17 to 1.40, I2=74%, n=28, low certainty) for ever, 1.29 (95% CI 1.03 to 1.62, I2=84%, n=19) for current and 1.25 (95% CI 1.11 to 1.42, I2=75%, n=14) for former smokers compared with never smokers. The absolute risk of COVID-19 death was increased by 14%, 11%, 12% and 7% for diabetes, hypertension, obesity and smoking, respectively. The proportion of deaths attributable to diabetes, hypertension, obesity and smoking was 8%, 7%, 11% and 2%, respectively.ConclusionOur findings suggest that diabetes, hypertension, obesity and smoking were associated with higher COVID-19 mortality, contributing to nearly 30% of COVID-19 deaths.Trial registration numberCRD42020218115.

Background Perturbations in circulating metabolites prior to a breast cancer diagnosis are not well characterised. We aimed to gain more detailed knowledge to help understand and prevent the disease. Methods Baseline plasma samples from 791 breast cancer cases and 791 matched controls from the E3N (EPIC-France) cohort were profiled by nuclear magnetic resonance (NMR)-based untargeted metabolomics. Partial least-squares discriminant analysis (PLS-DA) models were built from NMR profiles to predict disease outcome, and odds ratios and false discovery rate (FDR)-adjusted CIs were calculated for 43 identified metabolites by conditional logistic regression. Results Breast cancer onset was predicted in the premenopausal subgroup with modest accuracy (AUC 0.61, 95% CI: 0.49–0.73), and 10 metabolites associated with risk, particularly histidine (OR = 1.70 per SD increase, FDR-adjusted CI 1.19–2.41), N-acetyl glycoproteins (OR = 1.53, FDR-adjusted CI 1.18–1.97), glycerol (OR = 1.55, FDR-adjusted CI 1.11–2.18) and ethanol (OR = 1.44, FDR-adjusted CI 1.05–1.97). No predictive capacity or significant metabolites were found overall or for postmenopausal women. Conclusions Perturbed metabolism compared to controls was observed in premenopausal but not postmenopausal cases. Histidine and NAC have known involvement in inflammatory pathways, and the robust association of ethanol with risk suggests the involvement of alcohol intake.

Measures implemented in many countries to contain the COVID-19 pandemic resulted in a change in lifestyle with unpredictable consequences on physical and mental health. We aimed at identifying the variables associated with psychological distress during the lockdown between April and May 2020 in the Italian academic population. We conducted a multicenter cross-sectional online survey (IO CONTO 2020) within five Italian universities. Among about 240,000 individuals invited to participate through institutional communications, 18 120 filled the questionnaire. Psychological distress was measured by the self-administered Hospital Anxiety and Depression Scale (HADS). The covariates collected included demographic and lifestyle characteristics, trust in government, doctors and scientists. Associations of covariates with influenza-like symptoms or positive COVID-19 test and with psychological distress were assessed by multiple regression models at the local level; a meta-analysis of the results was then performed. Severe levels of anxiety or depression were reported by 20% of the sample and were associated with being a student or having a lower income, irrespective of their health condition and worries about contracting the virus. The probability of being severely anxious or depressed also depended on physical activity: compared to those never exercising, the highest OR being for those who stopped during lockdown (1.53; 95% CI, 1.28 to 1.84) and the lowest for those who continued (0.78; 95% CI, 0.64 to 0.95). Up to 21% of severe cases of anxiety or depression might have been avoided if during lockdown participants had continued to exercise as before. Socioeconomic insecurity contributes to increase mental problems related to the COVID-19 pandemic and to the measures to contain it. Maintaining or introducing an adequate level of physical activity is likely to mitigate such detrimental effects. Promoting safe practice of physical activity should remain a public health priority to reduce health risks during the pandemic.

Background Diet is a modifiable risk factor for non-communicable diseases which are the major causes of death worldwide. French dietary guidelines, updated in 2017, provide recommendations for a healthier diet. We aimed to study the association between adherence to these dietary guidelines and mortality in the E3N (Etude Epidémiologique auprès de femmes de l'Education Nationale) French cohort. A secondary objective was to investigate the role of dietary exposure to chemical contaminants in this association. Methods We studied 72 585 women of the E3N prospective cohort, which completed a food frequency questionnaire in 1993. We estimated adherence to French dietary guidelines using the simplified “ Programme National Nutrition Santé —guidelines score 2” (sPNNS-GS2, range -20.4 to 12.6). We estimated the association between sPNNS-GS2 and all-cause or cause-specific mortality using Cox proportional hazard models. Causes of death were coded and validated by the French Epidemiology Center on Medical Causes of Death (Inserm-CépiDc). Results During follow-up (1993–2014), we identified 6 441 deaths. The mean sPNNS-GS2 was 3.8 (SD 3.0). In the fully adjusted model, we found a non-linear association between sPNNS-GS2 and all-cause, all-cancer, breast cancer and lung cancer mortality ( p -values for the overall association < 0.001), with a diminution of the risk as sPNNS-GS2 increases up to its median or 65 th percentile (depending on the outcome), and then a plateau (for all-cause and breast cancer mortality) or an inversion of the trend (for all-cancer and lung cancer mortality). Furthermore, we identified a linear inverse association with cardiovascular diseases mortality (HR oneSTD [95%CI]: 0.86 [0.76; 0.97]), and no association with colorectal cancer mortality. We observed similar results when additionally adjusting on dietary exposure to chemical contaminants. Conclusions This study conducted in a large prospective cohort following more than 70 000 women for over 20 years suggested that higher adherence to French dietary guidelines was associated with a reduced risk of mortality from all-cause, cardiovascular diseases, all-cancer, breast cancer, and lung cancer, except for high values of adherence for lung cancer mortality. These results contribute to informing on the importance of following the French nutritional recommendations.

Persistent organic pollutants (POPs) are a group of organic chemical compounds. Contradictory results have emerged in epidemiological studies attempting to elucidate their relationship with breast cancer risk. This study explored the relationship between dietary exposures to multiple POPs and ER-positive breast cancer risk in the French E3N cohort study, using three different approaches to handle multicollinearity among exposures. Intakes of 81 POPs were estimated using food consumption data from a validated semi-quantitative food frequency questionnaire and food contamination data. In the first approach, hierarchical clustering was performed to identify clusters of correlated POPs. For each cluster, the levels of POPs belonging to it were averaged. These average levels were then included in a Cox model to estimate their associations with ER-positive breast cancer occurrence. The second and third approaches applied in the present study were Principal component Cox regression (PCR-Cox) and partial least squares Cox regression (PLS-Cox) respectively, both being dimension-reduction methods (respectively unsupervised and supervised) coupled to a Cox model, used to identify principal components of POPs and to estimate their associations with ER-positive breast occurrence. All models were adjusted for potential confounders previously identified using a directed acyclic graph. The study included 66,722 women with a median follow-up of 20.3 years, during which 3,739 developed an incident ER-positive breast cancer. The variable clustering method did not identify any association between the averaged variables and ER-positive breast cancer risk. Five components were retained using both the PCR-Cox and PLS-Cox methods explaining 82% and 77% of the variance in the initial exposure matrix respectively. Among these components, none was significantly associated with the occurrence of ER-positive breast cancer. This study provides an illustrative example of the application of three distinct statistical methods in the context of highly correlated environmental exposures, discussing their potential relevance and limitations within this specific framework.

Molecular studies suggest that cadmium due to its estrogenic properties, might play a role in breast cancer (BC) progression. However epidemiological evidence is limited. This study explored the association between long-term exposure to airborne cadmium and risk of BC by stage, grade of differentiation, and histological types at diagnosis. A nested case–control study of 4401 cases and 4401 matched controls was conducted within the French E3N cohort. A Geographic Information System (GIS)-based metric demonstrated to reliably characterize long-term environmental exposures was employed to evaluate airborne exposure to cadmium. Multivariable adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. There was no relationship between cadmium exposure and stage of BC. Also, no association between cadmium exposure and grade of differentiation of BC was observed. However, further analyses by histological type suggested a positive association between cadmium and risk of invasive tubular carcinoma (ITC) BC [OR Q5 vs Q1  = 3.4 (95% CI 1.1–10.7)]. The restricted cubic spline assessment suggested a dose–response relationship between cadmium and ITC BC subtype. Our results do not support the hypothesis that airborne cadmium exposure may play a role in advanced BC risk, but suggest that cadmium may be associated with an increased risk of ITC.

The involvement of mucosa associated lymphoid tissues (MALT) in the development of an autoimmune response in the skin is unclear and unstudied. In this study we sought to assess the relationship between removal of MALT tissues (MALTectomy) and the risk of development of psoriasis (overall or moderate-to-severe). We conducted a prospective observational study based on E3N, a French cohort composed of 98 995 women born between 1925 and 1950 and insured by the health insurance of the national education system (MGEN). The study population included the 90 119 women that completed the 1990 baseline questionnaire with available information on MALTectomy and a valid incident diagnostic date for psoriasis. During the 1990-2018 follow-up period 2 433 incident cases of psoriasis were identified through self-reports while during the period for which drug reimbursement data were available from the MGEN database (2004-2018), 120 cases of moderate-to-severe psoriasis were identified. Hazard ratios (HR) and their 95% confidence intervals were estimated by Cox proportional hazards models and adjusted for known or putative psoriasis risk factors. Appendectomy was associated with an increased risk of psoriasis both in the univariate [HR: 1.17 (95% CI: 1.08-1.27)] and multivariable models [HR: 1.14 (95% CI: 1.05-1.24)]. A suggestive association with appendectomy was observed for moderate-to-severe psoriasis risk [univariate HR: 1.40 (95%CI: 0.97-2.02); multivariable HR: 1.36 (95%CI: 0.94-1.96)]. No association was observed between tonsillectomy or adenoidectomy both for overall and moderate-to-severe psoriasis. The observed association between appendectomy and risk of psoriasis warrants further investigations as they may help to elucidate the disease etiology and improve risk prediction.

Background Growing epidemiological evidence suggests an association between exposure to air pollutants and breast cancer. Yet, the underlying mechanisms remain poorly understood. This study explored the mediating role of thirteen metabolic health biomarkers in the relationship between exposure to three air pollutants, i.e. nitrogen dioxide (NO 2 ), polychlorinated biphenyls 153 (PCB153), and benzo[a]pyrene (BaP), and breast cancer risk. Methods We used data from a nested case–control study within the French national prospective E3N-Generations cohort, involving 523 breast cancer cases and 523 matched controls. The four-way decomposition mediation of total effects for thirteen biomarkers was applied to estimate interaction and mediation effects (controlled direct, reference interaction, mediated interaction, and pure indirect effects). Results The analyses indicated a significant increase in breast cancer risk associated with BaP exposure (odds ratio (OR) Q4 vs Q1  = 2.32, 95% confidence intervals (CI): 1.00–5.37). PCB153 exposure showed a positive association only in the third quartile (OR Q3 vs Q1  = 2.25, CI 1.13–4.57), but it appeared to be non-significant in the highest quartile (OR Q4 vs Q1  = 2.07, CI 0.93–4.61). No association was observed between NO 2 exposure and breast cancer risk. Estradiol was associated with an increased risk of breast cancer (OR per one standard deviation (SD) increment = 1.22, CI 1.05–1.42), while thyroid-stimulating hormone was inversely related to breast cancer risk (OR per 1SD increase = 0.87, CI 0.75–1.00). We observed a suggestive mediated effect of the association between the three pollutants and breast cancer risk, through albumin, high-density lipoproteins cholesterol, low-density lipoprotein cholesterol, parathormone, and estradiol. Conclusion Although limited by a lack of statistical power, this study provides relevant insights into the potential mediating role of certain biomarkers in the association between air pollutant exposure and breast cancer risk, highlighting the need for further in-depth studies in large populations.

BackgroundThe evidence linking ambient air pollution to bladder cancer is limited and mixed.MethodsWe assessed the associations of bladder cancer incidence with residential exposure to fine particles (PM2.5), nitrogen dioxide (NO2), black carbon (BC), warm season ozone (O3) and eight PM2.5 elemental components (copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc) in a pooled cohort (N = 302,493). Exposures were primarily assessed based on 2010 measurements and back-extrapolated to the baseline years. We applied Cox proportional hazard models adjusting for individual- and area-level potential confounders.ResultsDuring an average of 18.2 years follow-up, 967 bladder cancer cases occurred. We observed a positive though statistically non-significant association between PM2.5 and bladder cancer incidence. Hazard Ratios (HR) were 1.09 (95% confidence interval (CI): 0.93–1.27) per 5 µg/m3 for 2010 exposure and 1.06 (95% CI: 0.99–1.14) for baseline exposure. Effect estimates for NO2, BC and O3 were close to unity. A positive association was observed with PM2.5 zinc (HR 1.08; 95% CI: 1.00–1.16 per 10 ng/m3).ConclusionsWe found suggestive evidence of an association between long-term PM2.5 mass exposure and bladder cancer, strengthening the evidence from the few previous studies. The association with zinc in PM2.5 suggests the importance of industrial emissions.