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Pancreatic Cancer: How to identify high-risk populationNúria MalatsCentro Nacional de Investigaciones Oncológicas (CNIO)[email protected] 2017 / NMalats1

PancreasThe FactsEDCD 2017 / NMalats5

Looking into the future: hoping to be wrongPancreasEDCD 2017 / NMalats3

Death rates from pancreatic cancer are rising whilerates for all other cancers continue to fall in EuropePancreasPancreatic CancerMoredeaths from pancreatic cancerPERSONALIZED PREVENTION OFthanPANCREATICCANCERbreast cancer in the EU by 2017Malvezzi M, Ann Oncol 2014EDCD 2017 / NMalatsFerlay J, Acta Oncol 20164

Pancreatic Cancer Aetiology: Complex64% attributed to environmental factorsPancreas(Lichtenstein P et al. NEJM 2000)Sporadic cancerFamilial , MSH2, MSH6APCPALB2PRSS1, SPIN1CFTRKlein et al. Mol Carcinog 2012EDCD 2017 / NMalats5

Anticipating Pancreatic Cancer : Complex ?General PopulationLifetime PC risk 0.7%High-risk90%sporadic8%FPC2%HPCLifetime PC risk 16 %EDCD 2017 / NMalats6

PANCREATIC CANCER: A chronic inflammation-related diseasePancreasSeleniumVitamin DMetals(Cd, As, Pb)HelicobacterpyloriTobaccoPAF 11-32%DiabetesPAF 1-16%ChronicpancreatitisPAF 3%PeriodontitisObesityPAF 3-16%A/BBlood groupPAF 13-19%StatinsMetforminAlcoholPAF 9%PANCREASCANCERFamilyhistoryPAF 3-10%ASANSAIDsAllergy/AsthmaPAF 3-7%PAF: Population Attributable FractionLowenfels et al. Int J Epidemiol 2015GENOMEEDCD 2017 / NMalatsEPIGENOMEMICROBIOME7

Enriching pancreatic cancer high-risk population: 2-step filterScreening withEDCD 2017 / NMalats8

European Study of Chronic Pancreas Diseases and GeneticPanGenEU Study Hospital-based case-control and cohort study Consensus pathology review Samples (uniform SOPs) Blood Saliva Urine Toenails Tissue Stool Information (EPIQUEST) Epidemiologic Clinical-pathological Prospective follow-upFrom 2009 to 201328 centresCasesControlsInformed consent22991450Epi questionnaire22461304Clinical &FU 6669ToenailsExternal Scientific Advisors:D Silverman (NCI, USA)D Easton (Cambridge U, UK)EDCD 2017 / NMalats9

PANCREATIC CANCER EXPOSOMEPancreasSeleniumVitamin DMetals(Cd, As, Pb)HelicobacterpyloriObesityTobaccoA/BBlood titisPeriodontitisFamilyhistoryEDCD 2017 / -Rubio et al. Gut 201710

Multimorbidity patterns and pancreatic cancer riskTime-dependencePancreas2yrLongstanding conditionLongstanding ConditionsCasesControlsN 1705N ecent conditionCasesControlsN 1318N 103773029219010661023513458OR*95%CIRecent ConditionsCasesControlsN 1009N 64073019386610219OR*95%CIGastric Diabetes 012 3P. of trend11.972.483.51.58 - 2.471.87 - 3.292.38 - 5.134.39E-1411.29 1.02 – 1.651.56 1.15 – 2.122.39 1.58 - 2.652.02E-0518.76 5.37 – 14.2710 4.79 – 20.961.14E-20 Heartburn, Acid regurgitation, H. pylori, Ulcer, and T2D* Adjusted for age, sex, country, pack/years, and number of morbidities† Last two categories combined into one ( 2 conditions). Subjects with 3 conditions: 13 cases and 3 controlsRisk factorsEDCD 2017 / NMalatsEarly manifestations ?Gómez-Rubio et al. Ann Oncol 201711

Autoimmune disease and pancreatic cancer riskPancreasOR, 95%CIAny AID1 AID 2 AIDsSystemicLocalizedBothGI AIDsPanGenEU Study1705 cases & 1084 controlshttp://www.disgenet.org/web/DisGeNETEDCD 2017 / NMalatsGómez-Rubio et al. Submitted12

PANCREATIC CANCER and GENOMEPancreasSeleniumVitamin DMetals(Cd, As, Pb)HelicobacterpyloriObesityTobaccoA/BBlood NCERAllergy/AsthmaGENOMEEDCD 2017 / NMalats13

PANCREATIC CANCER and tir L. Int J Biol Sci 2016EDCD 2017 / NMalats14

PANCREATIC CANCER and GENOMEPancreasSeleniumVitamin DMetals(Cd, As, Pb)HelicobacterpyloriObesityTobaccoA/BBlood NCERAllergy/AsthmaGENOMEBlood(SNP, CNV, Rare variants)GWAS (PanGenEU)WES/WGS (ICGC)EDCD 2017 / NMalatsLópez de Maturana E, et al. Work in progress15

PANCREATIC CANCER and METHYLATIONPancreasSeleniumVitamin DMetals(Cd, As, Pb)HelicobacterpyloriObesityTobaccoA/BBlood EBlood(SNP, CNV, Rare variants)GWAS (PanGenEU)WES/WGS (ICGC)EDCD 2017 / 850K IlluminaCol. M Fraga, UNIOVIAlonso L, et al. Work in progress16

PANCREATIC CANCER and MICROBIOMEPancreasSeleniumVitamin DMetals(Cd, As, Pb)HelicobacterpyloriObesityTobaccoA/BBlood EBlood(SNP, CNV, Rare variants)GWAS (PanGenEU)WES/WGS (ICGC)EDCD 2017 / 850K IlluminaCol. M Fraga, UNIOVIMICROBIOMEOral – Gut(pathogens)MetaG, 16SCol. P Bork, EMBLMolina E & Gómez P. Work in progress17

Multifactorial PANCREATIC CANCER aetiologyPancreasSeleniumVitamin DMetals(Cd, As, Pb)HelicobacterpyloriObesityTobaccoA/BBlood EBlood(SNP, CNV, Rare variants)GWAS (PanGenEU)WES/WGS (ICGC)EDCD 2017 / 850K IlluminaCol. M Fraga, UNIOVIMICROBIOMEOral – Gut(pathogens)MetaG, 16SCol. P Bork, EMBLMolina E & Gómez P. Work in progress18

Take-home Messages1. Pancreatic cancer aetiology is complex with highly-correlated genomicand non-genomic factors involved2. Definition of high-risk populations should mirror such complexity bybuilding multifactorial algorithms3. Multimorbidity patterns associate with pancreatic cancer, highlightingthe importance of the systems concept (diseasome)4. Hyper-reactivity of the immune system (asthma, allergies, andautoimmune diseases) reduces the risk of pancreatic cancer5. Medical conditions included in the multimorbidity patterns have acommon genetic background partly shared with pancreatic cancer6. Genomics, methylomics, and microbiomics patterns associated withpancreatic cancer riskEDCD 2017 / NMalats19

Anticipating Pancreatic Cancer : Complex ?General PopulationLifetime PC risk 0.7%90%sporadicHigh-risk8%FPC2%HPCLifetime PC risk 16 %High-risk population:- Precursor Conditions (NODM, Chronic pancreatitis)- Precursor Lesions (IPMN)- Risk/Protective FactorsEDCD 2017 / NMalats20

Larger investment in primary & secondary preventionPresent/Future challenges in pancreatic cancer aetiology research Need to apply a “systems thinking” Large & international standardized studies Longitudinal data and sample collection e-medical records novel “smart” technologies: e-exposures associated biobanks using same SOPs Omics data generation: adequate platforms Next-generation database platforms and Quantum-computing Algorithms allowing Omics and non-omics data integration Multidisciplinary approaches involving health professionalsEDCD 2017 / NMalats21

AcknowledgmentsMultimorbidity studies InvestigatorsPanGenEU StudyV RosatoA GutierrezC BosettiJ PiñeroC La VecchiaL FurlongChronic Pancreatitis Team: D Whitcomb, L Amundadottir, MLehr, W Greenhalf, A Ferré, X MoleroCNIO, Madrid (Genetic and Molecular Epidemiology, EpithelialCarcinogenesis (FX Real), Structural Computational Biology,Bioinformatics Unit, Human Genotyping Unit-CEGEN)Institut Municipal d’Investigació Mèdica, BarcelonaHospital del Mar, Barcelona (I Poves, L Ilzarbe)Hospital de Sant Pau, Barcelona (A Farré)Hospital Vall d‘Hebron, Barcelona (X Molero, L Guarner)Hospital Universitario de Oviedo (A Tardón)Hospital CLínico de Salamanca (L Muñoz-Bellvis)Hospital Universitario de Santiago C. (E Dominguez-Muñoz)Hospital Universitario de Elche (V Barberá)Hospital 12 de Octubre, Madrid (P Peláez)Hospital Ramón y Cajal, Madrid (A Carrato)Centro Oncológico Integral “Clara Campal”, Madrid (M Hidalgo)Philipps-Universität Marburg (T Gress, M Buchholz)Technische Universität Munchen (C Michalski)University of Liverpool (B Greenhalf)Queen Mary University of London (T Crnogorac-Jurcevic)Universita di Verona (A Scarpa, R Lawlor)Karolinska Institute, Stockholm (M Löhr)PanCAM, Ireland (L Sharp, L Murray)External Scientific Advisors: D Silverman (NCI,US), D Easton (Sanger, UK)Patients, monitors, technicians, doctors, and researchersPancreas cancer studies collaboratorsMicrobiome: P Bork (EMBL, Germany)Methylome: M Fraga (UniOvi, Spain)ICGC: A Biankin (Glasgow U, UK), S Gallinger (OICR, Canada)PanGenFAM: A Carrato (HRyC, Spain)Pancreatic Cancer Europe // PancreOS RegistryPANSCAN & PanC4: L Amundadottir (NCI, US), G Petersen(Mayo C, US), A Klein(JHU, US)EUPancreas COST ActionVice-Chair: C La Vecchia (U. Milan, Italy)WG Coordinators: I Esposito (U. Düsseldorf, Germany), KVan Steen (U. Liège, Belgium), S Hahn (U. Bohum), A Brand(U Maastricht)Action coordination: E Molina (CNIO, Spain)22

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PANCREATIC CANCER and sChronicpancreatitisPeriodontitisNeisseria elongataStreptococcus mitisCRG 2017 / cter actinomycetemcomitansPhylum FusobacteriaLeptotrichia24