pancreatic cancer: how to identify high-risk population · pancreatic cancer: how to identify...
TRANSCRIPT
Pancreatic Cancer: How to identify high-risk population
Núria Malats
Centro Nacional de Investigaciones Oncológicas (CNIO)
1EDCD 2017 / NMalats
The Facts
Pancreas
5EDCD 2017 / NMalats
Looking into the future: hoping to be wrong
Pancreas
3EDCD 2017 / NMalats
Death rates from pancreatic cancer are rising while rates for all other cancers continue to fall in Europe
Malvezzi M, Ann Oncol 2014
Pancreatic Cancer
Ferlay J, Acta Oncol 2016
More deaths from pancreatic cancerthan breast cancer in the EU by 2017
4
PERSONALIZED PREVENTION OF PANCREATIC CANCER
Pancreas
EDCD 2017 / NMalats
90%sporadic
2%HPC
8%FPC
Pancreatic Cancer Aetiology: Complex
Sporadic cancer
Familial (unknown)
BRCA2
CDKN2A
STK11
MLH1, MSH2, MSH6
APC
PALB2
PRSS1, SPIN1
CFTR
Klein et al. Mol Carcinog 2012
64% attributed to environmental factors(Lichtenstein P et al. NEJM 2000)
5
Pancreas
EDCD 2017 / NMalats
90%sporadic
2%HPC
8%FPC
Lifetime PC risk >16 %
Anticipating Pancreatic Cancer : Complex ???
High-risk
General Population
Lifetime PC risk = 0.7%
6EDCD 2017 / NMalats
GENOME
Periodontitis
PANCREASCANCER
Diabetes
A/BBlood group
Chronic pancreatitis
TobaccoObesity
Metals(Cd, As, Pb)
Allergy/Asthma
Vitamin D
Helicobacter pylori
StatinsMetformin
Selenium
Alcohol
ASANSAIDs
Familyhistory
MICROBIOME
Pancreas
EPIGENOME
PANCREATIC CANCER: A chronic inflammation-related disease
7
PAF: Population Attributable FractionLowenfels et al. Int J Epidemiol 2015
PAF<3%
PAF=1-16%
PAF=3-16%PAF=11-32%
PAF=13-19%
PAF=3-7%
PAF<9%
PAF=3-10%
EDCD 2017 / NMalats
Screening with
Enriching pancreatic cancer high-risk population: 2-step filter
8EDCD 2017 / NMalats
• 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-up
From 2009 to 201328 centres
External Scientific Advisors: D Silverman (NCI, USA)D Easton (Cambridge U, UK)
Cases Controls
Informed consent 2299 1450
Epi questionnaire 2246 1304
Clinical &FU data 1175 -
Blood 2036 1350
Saliva 1319 1008
Urine 1608 950
Toenails 636 669
European Study of Chronic Pancreas Diseases and Genetic
PanGenEU Study
9EDCD 2017 / NMalats
Periodontitis
PANCREASCANCER
Diabetes
A/BBlood group
Chronic pancreatitis
TobaccoObesity
Metals(Cd, As, Pb)
Allergy/Asthma
Vitamin D
Helicobacter pylori
StatinsMetformin
Selenium
Alcohol
ASANSAIDs
Familyhistory
Pancreas
PANCREATIC CANCER EXPOSOME
10Gómez-Rubio et al. Gut 2017EDCD 2017 / NMalats
Longstanding Conditions Recent Conditions
Cases Controls OR* 95%CI Cases Controls OR* 95%CI Cases Controls OR* 95%CI
N=1705 N=1084 N=1318 N=1037 N=1009 N=640
Gastric + Diabetes^
0 730 610 1 730 610 1 730 610 11 482 256 1.97 1.58 - 2.47 292 235 1.29 1.02 – 1.65 193 21 8.76 5.37 – 14.272 322 150 2.48 1.87 - 3.29 190 134 1.56 1.15 – 2.12 86 9 10 4.79 – 20.96
>=3 171 68 3.5 2.38 - 5.13 106 58 2.39 1.58 - 2.65P. of trend 4.39E-14 2.02E-05 1.14E-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 controls
PANCREASCANCERLongstanding condition
2yr
Recent condition
Multimorbidity patterns and pancreatic cancer risk Time-dependence
Early manifestations ?Risk factors
Gómez-Rubio et al. Ann Oncol 2017
Pancreas
11EDCD 2017 / NMalats
Pancreas
http://www.disgenet.org/web/DisGeNET
Autoimmune disease and pancreatic cancer risk
Gómez-Rubio et al. Submitted
Any AID
1 AID
>2 AIDs
Systemic
Localized
Both
GI AIDs
PanGenEU Study1705 cases & 1084 controls
OR, 95%CI
12EDCD 2017 / NMalats
GENOME
Periodontitis
PANCREASCANCER
Diabetes
A/BBlood group
Chronic pancreatitis
TobaccoObesity
Metals(Cd, As, Pb)
Allergy/Asthma
Vitamin D
Helicobacter pylori
StatinsMetformin
Selenium
Alcohol
ASANSAIDs
Familyhistory
Pancreas
PANCREATIC CANCER and GENOME
13EDCD 2017 / NMalats
14
Amundadottir L. Int J Biol Sci 2016
Pancreas
PANCREATIC CANCER and GENOME
https://www.ebi.ac.uk/gwas/
EDCD 2017 / NMalats
Periodontitis
PANCREASCANCER
Diabetes
A/BBlood group
Chronic pancreatitis
TobaccoObesity
Metals(Cd, As, Pb)
Allergy/Asthma
Vitamin D
Helicobacter pylori
StatinsMetformin
Selenium
Alcohol
ASANSAIDs
Familyhistory
Pancreas
GENOMEBlood
(SNP, CNV, Rare variants)
GWAS (PanGenEU)WES/WGS (ICGC)
PANCREATIC CANCER and GENOME
15López de Maturana E, et al. Work in progressEDCD 2017 / NMalats
Periodontitis
PANCREASCANCER
Diabetes
A/BBlood group
Chronic pancreatitis
TobaccoObesity
Metals(Cd, As, Pb)
Allergy/Asthma
Vitamin D
Helicobacter pylori
StatinsMetformin
Selenium
Alcohol
ASANSAIDs
Familyhistory
Pancreas
GENOMEBlood
(SNP, CNV, Rare variants)
GWAS (PanGenEU)WES/WGS (ICGC)
EPIGENOMEBlood
(mCpG)850K Illumina
Col. M Fraga, UNIOVI
PANCREATIC CANCER and METHYLATION
16Alonso L, et al. Work in progressEDCD 2017 / NMalats
Periodontitis
PANCREASCANCER
Diabetes
A/BBlood group
Chronic pancreatitis
TobaccoObesity
Metals(Cd, As, Pb)
Allergy/Asthma
Vitamin D
Helicobacter pylori
StatinsMetformin
Selenium
Alcohol
ASANSAIDs
Familyhistory
Pancreas
GENOMEBlood
(SNP, CNV, Rare variants)
GWAS (PanGenEU)WES/WGS (ICGC)
EPIGENOMEBlood
(mCpG)850K Illumina
Col. M Fraga, UNIOVI
MICROBIOMEOral – Gut
(pathogens)MetaG, 16S
Col. P Bork, EMBL
PANCREATIC CANCER and MICROBIOME
17Molina E & Gómez P. Work in progressEDCD 2017 / NMalats
Periodontitis
PANCREASCANCER
Diabetes
A/BBlood group
Chronic pancreatitis
TobaccoObesity
Metals(Cd, As, Pb)
Allergy/Asthma
Vitamin D
Helicobacter pylori
StatinsMetformin
Selenium
Alcohol
ASANSAIDs
Familyhistory
Pancreas
GENOMEBlood
(SNP, CNV, Rare variants)
GWAS (PanGenEU)WES/WGS (ICGC)
EPIGENOMEBlood
(mCpG)850K Illumina
Col. M Fraga, UNIOVI
MICROBIOMEOral – Gut
(pathogens)MetaG, 16S
Col. P Bork, EMBL
18Molina E & Gómez P. Work in progress
Multifactorial PANCREATIC CANCER aetiology
EDCD 2017 / NMalats
Take-home Messages1. Pancreatic cancer aetiology is complex with highly-correlated genomic
and non-genomic factors involved
2. Definition of high-risk populations should mirror such complexity bybuilding multifactorial algorithms
3. 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 cancer
5. Medical conditions included in the multimorbidity patterns have acommon genetic background partly shared with pancreatic cancer
6. Genomics, methylomics, and microbiomics patterns associated withpancreatic cancer risk
19EDCD 2017 / NMalats
90%sporadic
2%HPC
8%FPC
Lifetime PC risk >16 %
Anticipating Pancreatic Cancer : Complex ???
High-risk population:- Precursor Conditions (NODM, Chronic pancreatitis)- Precursor Lesions (IPMN)- Risk/Protective Factors
High-risk
General Population
Lifetime PC risk = 0.7%
20EDCD 2017 / NMalats
Larger investment in primary & secondary prevention
• 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 professionals
Present/Future challenges in pancreatic cancer aetiology research
21EDCD 2017 / NMalats
PanGenEU Study
CNIO, Madrid (Genetic and Molecular Epidemiology, Epithelial Carcinogenesis (FX Real), Structural Computational Biology, Bioinformatics Unit, Human Genotyping Unit-CEGEN)
Institut Municipal d’Investigació Mèdica, Barcelona
Hospital 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 researchers
Acknowledgments Multimorbidity studies InvestigatorsV Rosato A Gutierrez
C Bosetti J Piñero
C La Vecchia L Furlong
Chronic Pancreatitis Team: D Whitcomb, L Amundadottir, M Lehr, W Greenhalf, A Ferré, X Molero
Pancreas 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 Registry
PANSCAN & 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), K Van Steen (U. Liège, Belgium), S Hahn (U. Bohum), A Brand (U Maastricht)
Action coordination: E Molina (CNIO, Spain)
22
23
24 of September
Periodontitis
PANCREASCANCER
Diabetes
Chronic pancreatitis
Obesity
Allergy/Asthma
Helicobacter pylori
Pancreas
PANCREATIC CANCER and MICROBIOME
Neisseria elongataStreptococcus mitis
Porphyromona gingivalisMICROBIOME Porphyromona gingivalisAggregatibacter actinomycetemcomitansPhylum FusobacteriaLeptotrichia
24CRG 2017 / NMalats