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Air pollution has been associated with adverse health effects across the life-course. Although underlying mechanisms are unclear, several studies suggested pollutant-induced changes in transcriptomic profiles. In this meta-analysis of transcriptome-wide association studies of 656 children and adolescents from three European cohorts participating in the MeDALL Consortium, we found two differentially expressed transcript clusters (FDR p < 0.05) associated with exposure to particulate matter < 2.5 µm in diameter (PM2.5) at birth, one of them mapping to the MIR1296 gene. Further, by integrating gene expression with DNA methylation using Functional Epigenetic Modules algorithms, we identified 9 and 6 modules in relation to PM2.5 exposure at birth and at current address, respectively (including NR1I2, MAPK6, TAF8 and SCARA3). In conclusion, PM2.5 exposure at birth was linked to differential gene expression in children and adolescents. Importantly, we identified several significant interactome hotspots of gene modules of relevance for complex diseases in relation to PM2.5 exposure. ; European Community's 75 Seventh Framework Program under grant agreement numbers: 211250 (ESCAPE), and 76 261357 (MeDALL) ; European Research Council (grant agreement number 757919, TRIBAL) ; Swedish Research Council ; The Swedish Heart-Lung Foundation, Region Stockholm ; Strategic Research Programme (SFO) in Epidemiology, Karolinska Institutet ; Formas ; Swedish Environment Protection Agency ; Swedish Asthma and Allergy Research Foundation ; Cancer and Allergy Foundation ; Swedish Research Council for Health, Working life and Welfare (FORTE 2017-01146) ; Federal Ministry for Education, Science, Research and Technology ; Helmholtz Zentrum Munich ; Research Institute at Marien-Hospital Wesel, LMU Munich, TU Munich ; Leibniz Research-Institute for Environmental Medicine at the University of Düsseldorf ; Federal Ministry for Environment (IUF Düsseldorf, FKZ 20462296) ; Mead Johnson ; Nestlé ; Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI04/1436; PI06/0867; PI08/1151; and PI18/01142 ; Generalitat de Catalunya-CIRIT 1999SGR 00241 ; Department of Health of the Basque Government (2005111093) ; Provincial Government of Gipuzkoa (DFG06/002) ; Municipalities of the study area (Zumarraga, Urretxu , Legazpi, 101 Azkoitia y Azpeitia y Beasain) ; Accepted

Telomere length is considered a biomarker of biological aging. Shorter telomeres and obesity have both been associated with age-related diseases. To evaluate the association between various indices of obesity with leukocyte telomere length (LTL) in childhood, data from 1,396 mother-child pairs of the multi-centre European birth cohort study HELIX were used. Maternal pre-pregnancy body mass index (BMI) and 4 adiposity markers in children at age 8 (6-11) years were assessed: BMI, fat mass, waist circumference, and skinfold thickness. Relative LTL was obtained. Associations of LTL with each adiposity marker were calculated using linear mixed models with a random cohort effect. For each 1 kg/ m 2 increment in maternal pre-pregnancy BMI, the child's LTL was 0.23% shorter (95%CI: 0.01,0.46%). Each unit increase in child BMI z-score was associated with 1.21% (95%CI: 0.30,2.11%) shorter LTL. Inverse associations were observed between waist circumference and LTL (-0.96% per z-score unit; 95%CI: -2.06,0.16%), and skinfold thickness and LTL (-0.10% per z-score unit; 95%CI: -0.23,0.02%). In conclusion, this large multicentric study suggests that higher child adiposity indicators are associated with short telomeres in children, and that associations are stronger for child BMI than for maternal pre-pregnancy BMI. ; This work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 308333 - the HELIX project. INMA data collection was supported by grant C/from the Instituto de Salud Carlos III. This project has received funding from the European Union's Horizon 2020 research and innovation program under Grant Agreement No 774548. Tim S. Nawrot was funded by the EU Program "Ideas" (ERC-2012-StG 310898). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. We are grateful to all the participating families in the six countries who took part in this study. ; Vrijheid, M (reprint author), Inst Global Hlth Barcelona, ISGlobal, C Doctor Aiguader 88, Barcelona 08003, Spain, Univ Pompeu Fabra, Placa Merce 10, Barcelona 08002, Spain, CIBER Epidemiol & Salud Publ CIBERESP, Ave Monforte de Lemos 3-5, Madrid, Spain. martine.vrijheid@isglobal.org

Dyslipidemia and statin use have been associated with colorectal cancer (CRC), but prospective studies have shown mixed results. We aimed to determine whether dyslipidemia is causally linked to CRC risk using a Mendelian randomization approach and to explore the association of statins with CRC. A case-control study was performed including 1336 CRC cases and 2744 controls (MCC-Spain). Subjects were administered an epidemiological questionnaire and were genotyped with an array which included polymorphisms associated with blood lipids levels, selected to avoid pleiotropy. Four genetic lipid scores specific for triglycerides (TG), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), or total cholesterol (TC) were created as the count of risk alleles. The genetic lipid scores were not associated with CRC. The ORs per 10 risk alleles, were for TG 0.91 (95%CI: 0.72-1.16, p = 0.44), for HDL 1.14 (95%CI: 0.95-1.37, p = 0.16), for LDL 0.97 (95%CI: 0.81-1.16, p = 0.73), and for TC 0.98 (95%CI: 0.84-1.17, p = 0.88). The LDL and TC genetic risk scores were associated with statin use, but not the HDL or TG. Statin use, overall, was a non-significant protective factor for CRC (OR 0.84; 95%CI: 0.70-1.01, p = 0.060), but lipophilic statins were associated with a CRC risk reduction (OR 0.78; 95%CI 0.66-0.96, p = 0.018). Using the Mendelian randomization approach, our study does not support the hypothesis that lipid levels are associated with the risk of CRC. This study does not rule out, however, a possible protective effect of statins in CRC by a mechanism unrelated to lipid levels. ; This work was supported by the 'Acción Transversal del Cancer', approved by the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III, co-founded by FEDER funds –'a way to build Europe' [grants PI08/1770, PI08/0533, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/00613, PI17/00092 and PI15/00069]. Support was also provided by the Fundación Marqués de Valdecilla (grant API 10/09]; the Junta de Castilla y León [grant LE22A10-2]; the Consejería de Salud of the Junta de Andalucía [2009-S0143]; the Conselleria de Sanitat of the Generalitat Valenciana [grant AP 061/10]; the Recercaixa [grant 2010ACUP 00310]; the Regional Government of the Basque Country; the Consejería de Sanidad de la Región de Murcia; European Commission grants FOOD-CT-2006-036224-HIWATE; the Spanish Association Against Cancer (AECC) Scientific Foundation; the Catalan Government DURSI [grants 2017SGR723 and 2014SGR850]; the Fundación Caja de Ahorros de Asturias; the University of Oviedo; Societat Catalana de Digestologia; and COST action CA17118 Transcoloncan. ISGlobal and IDIBELL are members of the CERCA Programme, Generalitat de Catalunya.

A breast-risk score, published in 2016, was developed in white-American women using 92 genetic variants (GRS92), modifiable and non-modifiable risk factors. With the aim of validating the score in the Spanish population, 1,732 breast cancer cases and 1,910 controls were studied. The GRS92, modifiable and non-modifiable risk factor scores were estimated via logistic regression. SNPs without available genotyping were simulated as in the aforementioned 2016 study. The full model score was obtained by combining GRS92, modifiable and non-modifiable risk factor scores. Score performances were tested via the area under the ROC curve (AUROC), net reclassification index (NRI) and integrated discrimination improvement (IDI). Compared with non-modifiable and modifiable factor scores, GRS92 had higher discrimination power (AUROC: 0.6195, 0.5885 and 0.5214, respectively). Adding the non-modifiable factor score to GRS92 improved patient classification by 23.6% (NRI?=?0.236), while the modifiable factor score only improved it by 7.2%. The full model AUROC reached 0.6244. A simulation study showed the ability of the full model for identifying women at high risk for breast cancer. In conclusion, a model combining genetic and risk factors can be used for stratifying women by their breast cancer risk, which can be applied to individualizing genetic counseling and screening recommendations. ; The study was partially funded by the "Acción Transversal del Cancer" project, approved by the Spanish Council of Ministers on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PI09/00773-Cantabria, PI09/01286-León, PI09/01903-Valencia, PI09/02078-Huelva, PI09/01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219), by the Fundación Marqués de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) del ISCIII (RD12/0036/0036)), by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the Junta de Andalucía (2009-S0143), by the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), by the Recercaixa (2010ACUP 00310), by the Regional Government of the Basque Country, by the European Commission grants FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation and by the Catalan Government DURSI grant 2009SGR1489.

A breast-risk score, published in 2016, was developed in white-American women using 92 genetic variants (GRS92), modifiable and non-modifiable risk factors. With the aim of validating the score in the Spanish population, 1,732 breast cancer cases and 1,910 controls were studied. The GRS92, modifiable and non-modifiable risk factor scores were estimated via logistic regression. SNPs without available genotyping were simulated as in the aforementioned 2016 study. The full model score was obtained by combining GRS92, modifiable and non-modifiable risk factor scores. Score performances were tested via the area under the ROC curve (AUROC), net reclassification index (NRI) and integrated discrimination improvement (IDI). Compared with non-modifiable and modifiable factor scores, GRS92 had higher discrimination power (AUROC: 0.6195, 0.5885 and 0.5214, respectively). Adding the non-modifiable factor score to GRS92 improved patient classification by 23.6% (NRI = 0.236), while the modifiable factor score only improved it by 7.2%. The full model AUROC reached 0.6244. A simulation study showed the ability of the full model for identifying women at high risk for breast cancer. In conclusion, a model combining genetic and risk factors can be used for stratifying women by their breast cancer risk, which can be applied to individualizing genetic counseling and screening recommendations. ; The study was partially funded by the "Acción Transversal del Cancer" project, approved by the Spanish Council of Ministers on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PI09/00773-Cantabria, PI09/01286-León, PI09/01903-Valencia, PI09/02078-Huelva, PI09/01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219), by the Fundación Marqués de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) del ISCIII (RD12/0036/0036)), by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the Junta de Andalucía (2009-S0143), by the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), by the Recercaixa (2010ACUP 00310), by the Regional Government of the Basque Country, by the European Commission grants FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation and by the Catalan Government DURSI grant 2009SGR1489. ; Sí

The early-life exposome influences future health and accelerated biological aging has been proposed as one of the underlying biological mechanisms. We investigated the association between more than 100 exposures assessed during pregnancy and in childhood (including indoor and outdoor air pollutants, built environment, green environments, tobacco smoking, lifestyle exposures, and biomarkers of chemical pollutants), and epigenetic age acceleration in 1,173 children aged 7 years old from the Human Early-Life Exposome project. Age acceleration was calculated based on Horvath's Skin and Blood clock using child blood DNA methylation measured by Infinium HumanMethylation450 BeadChips. We performed an exposure-wide association study between prenatal and childhood exposome and age acceleration. Maternal tobacco smoking during pregnancy was nominally associated with increased age acceleration. For childhood exposures, indoor particulate matter absorbance (PMabs) and parental smoking were nominally associated with an increase in age acceleration. Exposure to the organic pesticide dimethyl dithiophosphate and the persistent pollutant polychlorinated biphenyl-138 (inversely associated with child body mass index) were protective for age acceleration. None of the associations remained significant after multiple-testing correction. Pregnancy and childhood exposure to tobacco smoke and childhood exposure to indoor PMabs may accelerate epigenetic aging from an early age ; The study received funding from the European Community's Seventh Framework Programme (FP7/2007-206) (grant agreement no 308333) (HELIX project), the H2020-EU.3.1.2. - Preventing Disease Programme (grant agreement no 874583) (ATHLETE project), and from the European Union's Horizon 2020 research and innovation programme (grant Agreement number: 733206) (Early Life stressors and Lifecycle Health (LIFECYCLE)). BiB received funding from the Welcome Trust (WT101597MA), from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) ...

Dyslipidemia and statin use have been associated with colorectal cancer (CRC), but prospective studies have shown mixed results. We aimed to determine whether dyslipidemia is causally linked to CRC risk using a Mendelian randomization approach and to explore the association of statins with CRC. A case-control study was performed including 1336 CRC cases and 2744 controls (MCC-Spain). Subjects were administered an epidemiological questionnaire and were genotyped with an array which included polymorphisms associated with blood lipids levels, selected to avoid pleiotropy. Four genetic lipid scores specific for triglycerides (TG), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), or total cholesterol (TC) were created as the count of risk alleles. The genetic lipid scores were not associated with CRC. The ORs per 10 risk alleles, were for TG 0.91 (95%CI: 0.72-1.16, p = 0.44), for HDL 1.14 (95%CI: 0.95-1.37, p = 0.16), for LDL 0.97 (95%CI: 0.81-1.16, p = 0.73), and for TC 0.98 (95%CI: 0.84-1.17, p = 0.88). The LDL and TC genetic risk scores were associated with statin use, but not the HDL or TG. Statin use, overall, was a non-significant protective factor for CRC (OR 0.84; 95%CI: 0.70-1.01, p = 0.060), but lipophilic statins were associated with a CRC risk reduction (OR 0.78; 95%CI 0.66-0.96, p = 0.018). Using the Mendelian randomization approach, our study does not support the hypothesis that lipid levels are associated with the risk of CRC. This study does not rule out, however, a possible protective effect of statins in CRC by a mechanism unrelated to lipid levels. ; This work was supported by the 'Acción Transversal del Cancer', approved by the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III, co-founded by FEDER funds –'a way to build Europe' [grants PI08/1770, PI08/0533, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/00613, PI17/00092 and PI15/00069]. Support was also provided by the Fundación Marqués de Valdecilla (grant API 10/09]; the Junta de Castilla y León [grant LE22A10-2]; the Consejería de Salud of the Junta de Andalucía [2009-S0143]; the Conselleria de Sanitat of the Generalitat Valenciana [grant AP 061/10]; the Recercaixa [grant 2010ACUP 00310]; the Regional Government of the Basque Country; the Consejería de Sanidad de la Región de Murcia; European Commission grants FOOD-CT-2006-036224-HIWATE; the Spanish Association Against Cancer (AECC) Scientific Foundation; the Catalan Government DURSI [grants 2017SGR723 and 2014SGR850]; the Fundación Caja de Ahorros de Asturias; the University of Oviedo; Societat Catalana de Digestologia; and COST action CA17118 Transcoloncan. ISGlobal and IDIBELL are members of the CERCA Programme, Generalitat de Catalunya. ; Sí

Purpose Essential to exposome research is the collection of data on many environmental exposures from different domains in the same subjects. The aim of the Human Early Life Exposome (HELIX) study was to measure and describe multiple environmental exposures during early life (pregnancy and childhood) in a prospective cohort and associate these exposures with molecular omics signatures and child health outcomes. Here, we describe recruitment, measurements available and baseline data of the HELIX study populations ; The research leading to these results has received funding from theb European Community's Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333—the HELIX project. Dr Maribel Casas and Dr Jordi Julvez received funding from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) (MS16/00128, MS14/00108). INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, the Conselleria de Sanitat, Generalitat Valenciana, Department of Health of the Basque Government; the Provincial Government of Gipuzkoa, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558), and NIH/NINDS (grant no. 1 UO1 NS 047537-01 and grant no. 2 UO1 NS 047537-06A1). The Rhea project was financially supported by European projects, and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011–2014; 'Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–2015). The work was also supported by MICINN (MTM2015-68140-R) and Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII. CW received funding from the Fondation de France ; SI

Background: Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes. Objectives: We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter <10 (PM10) or <2.5 mu m (PM2.5) and DNA methylation in newborns and children. Methods: We meta-analyzed associations between exposure to PM10 (n=1,949) and PM2.5 (n=1,551) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression. Results: Six CpGs were significantly associated [false discovery rate (FDR) <0.05] with prenatal PM10 and 14 with PM2.5 exposure. Two of the PM10-related CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant (p<0.05) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent PM10 exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal PM10 and or PM2.5 exposure, of which two PM10-related DMRs, including H19 and MARCH11, replicated in newborns. Conclusions: Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. ; ALSPAC: The UK Medical Research Council and the Wellcome Trust (Grant ref. 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and P.Y. will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristoLac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was specifically funded by a joint grant from the UK Economic & Social and Biotechnology & Biological Sciences Research Councils (Grant ref. ES/N000498/1). ALSPAC was funded by the BBSRC (BBI025751/1 and BB/I025263/1). Air pollution exposure assessment was funded by Public Health England as part of the MRC-PHE Centre for Environment and Health, funded also by the UK Medical Research Council (Grant ref. MR/L01341X/1). This paper does not necessarily reflect the views of Public Health England or the Department of Health. BAMSE was supported by The Swedish Research Council, The Swedish Heart-Lung Foundation, Freemason Child House Foundation in Stockholm, MeDALL (Mechanisms of the Development of ALLergy) a collaborative project conducted within the European Union (grant agreement No. 261357), Centre for Allergy Research, Stockholm County Council (ALE), Swedish Foundation for Strategic Research (SSF) (RBc08-0027), the Strategic Research Programme (SFO) in Epidemiology at Karolinska Institutet, The Swedish Research Council Foams, and the Swedish Environment Protection Agency. E.M. is supported by a grant from the European Research Council under the European Union (EU) Horizon 2020 (H2020) research and innovation programme (grant agreement number 757919, TRIBAL). O.G. is supported by Forte (Swedish Research Council for Health, Working Life and Welfare) and The Swedish Society for Medical Research. CHS: This work was supported by NIEHS grants K01ES017801, R01ES022216, and P30ES007048. EARLI: This work was supported by NIH grants R01ES016443, R01ES023780, and R01ES017646 as well as by Autism Speaks (AS 5938). ENVIRONAGE: The ENVIRONAGE birth cohort is funded by the European Research Counsil (ERC-2012-StG.310898) and by funds of the Flemisch Scientific Research Council (FWO, N1516112/G.0.873.11N.10). The methylation assays were funded by the European Community's Seventh Framework Programme FP7/2007-2013 project EXPOsOMICS (grant no. 308610). Z.H. is supported by the Exposomics EC FP7 grant (Grant agreement no. 308610). ZH and A.G. and the Epigenetics Group at IARC are supported by grants from the Institut National du Cancer (INCa, Plan Cancer-EVA-Inserm, France) and Association pour la Recherche sur le Cancer (ARC, France). Generation R Study: The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Center (MC), Rotterdam, the Erasmus University Rotterdam, Netherlands Organization for Health Research and Development and the Ministry of Health, Welfare and Sport. The EWAS data was funded by a grant to VWJ from Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project no. 050-060-810), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC. V.W.J. also received a grant from Netherlands Organization for Health Research and Development (VIDI 016.136.361) and a Consolidator Grant from the European Research Council (ERC-2014-CoG-648916). J.F.F. has received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement no. 633595 (DynaHEALTH). This project received funding from the European Union's Horizon 2020 Research and Innovation Programme (733206, LIFECYCLE). HELIX: The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 - the HELIX project. R.G. received the grant of the Lithuanian Agency for Science Innovation and Technology (No. 45 31V-66). The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558), NIH/NINDS (grant no. 1 UO1 NS 047537-01 and grant no. 2 UO1 NS 047537-06A1). INMA: This study was funded by grants from Institut() de Salud Carlos III (Red INMA G03/176), Generalitat de Catalunya-CIRIT 1999SGR 00241, and EU Commission (261357; 211250; 268479). Piccolipiu: The study was approved and initially funded by the Italian National Centre for Disease Prevention and Control (CCM grant 2010) and by the Italian Ministry of Health (art 12 and 12bis Dl.gs.vo 502/92). The methylation assays were funded by the European Community's Seventh Framework Programme FP7/2007-2013 project EXPOsOMICS (grant no. 308610). Z.H. is supported by the Exposomics EC FP7 grant (Grant agreement no: 308610). Z.H. and A.G. and the Epigenetics Group at IARC are supported by grants from the Institut National du Cancer (INCa, Plan Cancer-EVA-INSERM, France) and Association pour la Recherche sur le Cancer (ARC, France). Rhea: The methylation assays were funded by the European Community's Seventh Framework Programme FP7/2007-2013 project EXPOsOMICS (grant no. 308610). Z.H. is supported by the Exposomics EC FP7 grant (grant agreement no. 308610). ZH and A.G. and the Epigenetics Group at IARC are supported by grants from the Institut National du Cancer (INCa, Plan Cancer-EVA INSERM, France) and Association pour la Recherche sur le Cancer (ARC, France). PRISM: R.J.W. received funding for the PRISM cohort under HL095606 and R01 HL1143396. A.C.J. is supported by R00 ES023450. Project Viva: This Project Viva study was supported by grants from the NIH (NIH R01 HL 111108, R01 NR013945, R01 HD 034568, K24 HD069408, K23 ES022242, P01ES009825, R01AI102960, P30 ES000002) and the U.S. Environmental Protection Agency (EPA) (R832416, RD834798). This publication's contents are solely the responsibility of the grantee and do not necessarily represent the official views of the U.S. Government, the U.S. Department of Health and Human Services or the NIH, or the EPA. Further, the EPA does not endorse the purchase of any commercial products or services mentioned in the publication. MeDALL: The methylation study of MeDALL cohorts was funded by MEDALL, a collaborative project supported by the European Union under the Health Cooperation Work Programme of the 7th Framework Programme (grant agreement no. 261357). The Biobank-Based Integrative Omics Studies (BIOS) Consortium is funded by BBMRI-NL, a research 'infrastructure financed by the Dutch government (NWO 184.021.007). BAMSE: We would like to thank all the families for their participation in the BAMSE study. In addition, we would like to thank E. Haliner, S. Nilsson, and A. Lauber at the BAMSE secretary for invaluable support, as well as Mutation Analysis Facility (MAF) at Karolinska Institutet for genome-wide methylation analysis, and I. Delin for excellent technical assistance. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b201.4110.

Introduction: We present the protocol of a large population-based case-control study of 5 common tumors in Spain (MCC-Spain) that evaluates environmental exposures and genetic factors. Methods: Between 2008-2013, 10,183 persons aged 20-85 years were enrolled in 23 hospitals and primary care centres in 12 Spanish provinces including 1,115 cases of a new diagnosis of prostate cancer, 1,750 of breast cancer, 2,171 of colorectal cancer, 492 of gastro-oesophageal cancer, 554 cases of chronic lymphocytic leukaemia (CLL) and 4,101 population-based controls matched by frequency to cases by age, sex and region of residence. Participation rates ranged from 57% (stomach cancer) to 87% (CLL cases) and from 30% to 77% in controls. Participants completed a face-to-face computerized interview on sociodemographic factors, environmental exposures, occupation, medication, lifestyle, and personal and family medical history. In addition, participants completed a self-administered food-frequency questionnaire and telephone interviews. Blood samples were collected from 76% of participants while saliva samples were collected in CLL cases and participants refusing blood extractions. Clinical information was recorded for cases and paraffin blocks and/or fresh tumor samples are available in most collaborating hospitals. Genotyping was done through an exome array enriched with genetic markers in specific pathways. Multiple analyses are planned to assess the association of environmental, personal and genetic risk factors for each tumor and to identify pleiotropic effects. Discussion: This study, conducted within the Spanish Consortium for Biomedical Research in Epidemiology & Public Health (CIBERESP), is a unique initiative to evaluate etiological factors for common cancers and will promote cancer research and prevention in Spain ; The study was partially funded by the "Accion Transversal del Cancer", approved on the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PS09/00773, PS09/01286, PS09/01903, PS09/02078, PS09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150), by the Fundación Marqués de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL, by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the Junta de Andalucía (PI-0571), by the Conselleria de Sanitat of the Generalitat Valenciana (AP 061/10), by the Recercaixa (2010ACUP 00310), by the Regional Government of the Basque Country by European Commission grants FOOD-CT- 2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation, by the The Catalan Government DURSI grant 2009SGR1489