Liverpool Lung Project: development of a molecularepidemiological risk assessment model

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Liverpool Lung Project development of a
molecular-epidemiological risk assessment model

• Roy Castle Lung Cancer Research Programme

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Incidence of lung cancer (male)
Age-adjusted rate / 100,000r
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Trends in lung cancer incidence in males
U.K.
Croatia
Hungary
Denmark
ESR
Sweden
WHO 2003
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Incidence of lung cancer (female)
Age-adjusted rate / 100,000
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Trends in lung cancer incidence in females
U.K.
Hungary
Denmark

ESR
Sweden
Croatia
WHO 2003
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Comparative Incidence ratio by Sex NHS
Region, 1998
ONS, 2000
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Susceptibility
AgeGenderEthnic group
Genetic polymorphisms
Smoking
Diet
Health status
Environment
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The Liverpool Lung Project

• Increase understanding of interactions between
  different risk factors for lung cancer
• Individual risk assessment model for
  identification of high-risk individuals
• Identify early detection markers

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LLP Study Design

• Case-Control
• 500 cases - recruit via rapid access chest
  clinics
• Population controls (21) - matched for age and
  gender
• Entry criteria lung primary tumours

• Prospective Cohort
• 7500 subjects (age 45-79)
• Random selection from GP register, in study
  area
• 10 year follow-up

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SMR for electoral wards in Merseyside
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• Epidemiological Data Collection
• Lifestyle
• Diet
• Occupation
• Molecular Data Collection
• Blood sputum
• Tumour

Field JK and Youngson JH. The Liverpool Lung
Project a molecular epidemiological study of
early lung cancer detection. Eur Respir J 2002
20 1-16.
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Molecular Lung Tumour Markers Early Detection
Progression/Relapse Monitoring
Therapy Monitoring
Sputum/BL
Blood
Plasma serum
Microscopy In situ assays
Molecular Profile
DNA RNA Protein
Homogeneous assays
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Selection of High Risk Subset
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Previous Respiratory Disease

• Bronchitis or emphysema (BE)
• Bronchitis, emphysema or asthma (BEA)
• Bronchitis, emphysema or pneumonia (BEP)
• Bronchitis, emphysema, asthma or pneumonia (BEAP)
• Any Respiratory Disease (ANY)

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Smoking and History of BEP(lt60 years old)
BEP by case-control status and effect of BEP and
smoking status duration ( estimated 7 increase
in OR per year of smoking)
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Occupational Exposure
CEI 2000?djfjlj Example Asbestos
Intensity 1. gt background lt 50 OES 2. gt
50 lt150 OES 3. gt 150 OES Frequency 1. 5
min 0.5 hrs/day 2. 0.5 2.5 hrs/day 3. gt 2.5
hrs/day Confidence 1. exposure possible but
not . probable 2.
exposure probable 3. exposure certain
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Selected occupational exposures
ORa Adjusted for age, gender smoking p
lt0.05 plt0.01
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Air Pollution Modelling
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Refinement of Risk Genetic Susceptibility

• Hypothesize that there are several genetic
  modifiers that significantly increase the risk
  for developing lung cancer
• To date - polymorphisms in genes implicated in
  the major pathways of carcinogenesis carcinogen
  metabolism, DNA repair, cell cycle, apoptosis,
  and metastasis

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Molecular Biomarker Research
LLP
EU-ELC
DTI
Genotyping
Validation
DNA repair
Cell-cycle
Tumour Biology
Early Markers
Functional significance
Allelic Imbalance
Tumour/sputum/plasma
Organotypic Model
Tumour/sputum/plasma
Methylation
Expression
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Allelic Imbalance Analysis of Annual Plasma
Samples showing Increasing Levels of AI Towards
Clinical Diagnosis
Imbalance Factor
WBC
1.08
Plasma 1999
1.27
Plasma 2000
Plasma 2001
1.47
2001 positive lung Ca diagnosis
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Future disease management
Stratify individuals for risks
Epidemiology
Genotyping
Early detection of disease
Diseasespecific molecular markers
Stratify for therapeutic approach
Health Status
Personalised cure
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Conclusion

• Quantification of individual risk will lead to
  identification of high risk individuals to target
  early diagnosis programs
• - environmental and genetic components
• Molecular epidemiology offers new tools to
  epidemiological studies of lung cancer
• - etiology, mechanisms, clinical

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Acknowledgements
Department of Pathology John Gosney Chris
Foster Tom Giles
Roy Castle Programme Lakis Liloglou George
Xinarianos John Field
CR-UK Stephen Duffy Jonathan Miles Sequenom
Dirk van den Boom Mathias Ehrich Epigenomics S
Maier. Inko Nimmrich Matthias Burger Incyte,
USA Michael Donovan Amy Lasek Paula Ricket
Cardiothoracic Centre Martin Walshaw John
Drakely Ajaib Soorae Richard Page Neeraji
Mediratta
University of Manchester Martie van
Tongeren Richard Edwards
IARC Paolo Boffetta Paul Brennan
Fazakerley Hospital John Earis Robert Angus
Chris Warburton
Clatterbridge CO Peter Clark