Transcript PowerPoint Template

Genes, Biomarkers and Risk
Prediction for Barrett’s Oesophagus
Where are we now?
David Whiteman B Med Sc, MBBS (Hons), PhD, FAFPHM
Head, Cancer Control Group
24 May 2014
The issue
oesophagus
melanoma
prostate
breast
lung
colon
Pohl, H. et al. J Natl Cancer Inst 2005;97:142-146
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The challenges....
Person with
reflux
Development
of Barrett’s
metaplasia
Who has Barrett’s?
BO patient
low risk of progression
to cancer
Development
of cancer
BO patient
high risk of progression
to cancer
Who has a high risk
of developing
cancer?
Can we intervene to
reduce the risk of
cancer?
Some jargon
Person with
reflux
Development
of Barrett’s
metaplasia
SCREENING
BO patient
low risk of progression
to cancer
BO patient
high risk of progression
to cancer
SURVEILLANCE
Development
of cancer
Outline
Clinical factors
Biomarkers
Genetics
Lessons from Napoleon
Conclusions
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Clinical factors predicting OAC
Risk factors
Relative
risk
Prevalence
Male sex
6
50%
Frequent reflux
6
15%
Obesity
3
20%
Smoking
2
20%
Barrett’s
50
<2%
Fruit & veg
0.8
20%
H pylori
0.5
~25%
0.8
5%
0.9
7%
0.9
?10%
Age
Aspirin
PPI
Statins
?
?
?
Endoscopic/
Histologic
Segment length
Nodularity
Ulceration
Dysplasia
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Risk prediction
Thrift, Kendall, Pandeya and Whiteman, Clin Gastro Hepatol, 2013; 11:138–144
Are there biological factors that predict risk better than clinical factors?
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Biomarkers
• “A biological molecule found in blood, other body fluids, or tissues
that is a sign of a normal or abnormal process, or of a condition or
disease”.
• “A biomarker may be used to see how well the body responds to a
treatment for a disease or condition”.
Unstated:
must perform better than existing predictors
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Number of published articles on biomarkers in
Barrett’s esophagus from 1980 to 2011
Timmer et al. Diseases of the Esophagus (2013) 26, 574–581
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Phases of biomarker development
Preclinical
exploratory
PHASE 1 Promising directions identified
Clinical assay &
validation
PHASE 2 Clinical assay detects established disease
Retrospective
longitudinal
PHASE 3 Biomarker detects disease early before it becomes
clinical and a “screen positive” rule is defined
Prospective
screening
PHASE 4 Extent and characteristics of disease detected by the
test and the false referral rate are identified
Cancer Control
PHASE 5 Impact of screening on reducing the burden of
disease in the population are identified.
Early Detection Research Network (EDRN)
http://edrn.nci.nih.gov/
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Tissue
Blood
Fluids
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Biopsy
Tissue
Class
Biomarker
Phase
8-gene methylation panel
3
DNA content + LOH
4
LGD + aneuploidy + lectin
3
Aneuploidy/tetraploidy
4
Tumour suppressor
loci
P53 LOH
4
P16 staining
4
Proliferation
MCM2
3
Clonal diversity
DNA ploidy + LOH + microsatellite shifts
+ p53/p16 mutations
4
Cyclin A
3
Cyclin D1
3
P16 methylation
3
Biomarker panels
Blood
Fluids
DNA content
abnormality
Cell cycle markers
Epigenetics
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Biopsy
Tissue
Cytology
Blood
Barrett’s length
>1 cm
>2 cm
Sensitivity
73%
90%
Specificity
94%
94%
Fluids
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Tissue
DNA/RNA
Blood
Proteins
Fluids
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Tissue
Canada
DNA/RNA
Sweden
Ireland
Seattle Nebraska
Blood
USC
US multicenter
Kaiser
US black/white
Australia
Proteins
2400 BO cases
Fluids
1500 OAC cases
3200 controls
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Locus
Gene
P-value
3p13
FOXP1
5.5 x 10-9
9q22
BARX1
1.0 x 10-9
9q22
PTPDC1
5.8 x 10-9
19p13
CRTC1
3.6 x 10-10
19p13
CRTC1
1.8 x 10-9
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Is there any genetic overlap between reflux,
Barrett’s and oesophageal adenocarcinoma?
Reflux
Cancer
Barrett’s
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Tissue
Class
DNA/RNA
Serum biomarkers
Biomarker
Phase
Leukocyte telomere length
4
Selenoprotein P
4
Blood
Protein
Fluids
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Tissue
Blood
Fluids
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Dysplasia confirmed by two GI pathologists is currently the best tissue biomarker for the
assessment of cancer risk (Recommendation grade B).
Until randomised controlled evidence is available, biomarker panels cannot yet be
recommended as routine of care (Recommendation grade C).
The addition of p53 immunostaining to the histopathological assessment may improve the
diagnostic reproducibility of a diagnosis of dysplasia in Barrett’s oesophagus and should be
considered as an adjunct to routine clinical diagnosis (Recommendation grade C).
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Are we going about this the right way..?
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Are we going about this the right way..?
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Are we going about this the right way..?
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Are we going about this the right way..?
Screening biomarkers could act here
Surveillance biomarkers should act here
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Are we going about this the right way..?
Population Attributable Fraction (PAF)
0.76 (95% CI 0.66-0.84)
Olsen et al. Am J Epidemiol (2011) 174, 582-590.
Acknowledgements
QIMR – Epidemiology
David Whiteman
Penny Webb
David Purdie
Adele Green
QIMR – Cancer Genomics
Nick Hayward
Peter Parsons
Derek Nancarrow
University of Qld
David Gotley
John Prins
Project Managers
Suzanne Moore
Sue O’Brien
Research Nurses
Sue Brown
Cathy Baxter
Allison Forde
Chris Hill
Andrea McMurtrie Ellen Minehan
Deb Roffe
Linda Terry
Administrative Officers
Lynn Green
Barbara Ranieri
Databases
Karen Harrap
Troy Sadkowksy
Students
Shahram Sadeghi
Nirmala Pandeya
Kylie Smith
Aaron Thrift
Brad Kendall
Pathology
Andrew Clouston
Neal Walker
Ian Brown
Mark Smithers
Chris Bain
Graham Macdonald
Hayley Berry
Sue Lipshut
Gabby O’Connor
Janine Thomas
Michael Connard
Jeanette Mayhew
Sue Perry
Frances Walker
Clinical collaborators
NSW
Qld
SA
Vic
WA
Dr Garrett Smith and Prof Ross Smith
Dr Michael Kelly and A/Prof Denis King
Prof Christopher Martin and Dr Michael Cox
Dr Greg Falk
Dr Neil Merrett and Prof Stephen Deane
Dr Mike Hollands and Dr Roy Brancatisano
Royal North Shore
St George Hospital
Nepean Hospital
Concord Hospital
Liverpool Hospital
Westmead Hospital
Dr Les Nathanson and Dr Barry O’Loughlin
Dr Leigh Rutherford
Dr Ian Martin
Dr John Avramovic
Dr Gresham Clapham
Royal Brisbane Hospital
Gold Coast
Wesley
Townsville
Cairns
Prof Glyn Jamieson and Dr Peter Devitt
Prof David Watson and Dr Justin Bessell
Royal Adelaide Hospital
Flinders Medical Centre
Prof Robert Thomas
Mr George Kiroff
Mr Bruce Mann
Mr Stephen Blamey
Mr Andrew Smith
Mr Richard Cade
Mr Simon Woods
Peter MacCallum Cancer Institute
Geelong
Royal Melbourne Hospital
Monash Medical Centre
Alfred Hospital
Box Hill / Western / St Vncents
Cabrini Hospital
Mr Steve Archer
Mr Jeff Hamdorf
Mr David Fletcher
Mr Kingsley Faulkner
Mr Harry Sheiner
Royal Perth Hospital
Sir Charles Gairdner Hospital
Fremantle Hospital
WACOG
WACOG