Microbiome as a marker for CRC screening Dr Sunny H Wong MBChB (Hons), DPhil, MRCP, FHKCP, FHKAM (Medicine) Assistant Professor Institute of Digestive Disease Department of Medicine and Therapeutics WEO CRC Screening Committee Meeting
Microbiome as a marker for
CRC screening
Dr Sunny H WongMBChB (Hons), DPhil, MRCP, FHKCP, FHKAM (Medicine)
Assistant Professor
Institute of Digestive Disease
Department of Medicine and Therapeutics
WEO CRC Screening
Committee Meeting
Global burden of CRC
Incidence:
2nd cancer in female (~614 000)
3rd cancer in male (~746 000)
Mortality: 4th cancer (~694 000)
WHO 2015 and World Cancer Report 2014
Rationale of CRC screening
APC / KRAS Smad2/4 p53
Up to 10 years – can we catch it?
Screening reduces mortality
Jemal et al, Cancer J Clin 2008
Zauber et al, NEJM 2012
Before screening After screening
Colonoscopy is good, but…
• Requires expertise and high cost
• Bowel preparation
• Small but definite risk
• Patient preference
There is a need for non-invasive
screening biomarkers
Fecal occult blood markers
Guaiac fecal-occult blood test
(gFOBT)
• Detects heme
• Limited by
– Limited sensitivity (37-79%)
– Imperfect specificity
– Need for dietary restriction
Faecal immunochemical test
(FIT)
• Specific antibodies to globin
• Performance
– Sensitivity for CRC - 66-88%
– Sensitivity for AN - 27-54%
– Specificity 90-95%
• More specific for LGI bleeding
• Data across populations
Allison et al, NEJM 1996
Levi et al, Ann Intern Med 2007
Morikawa et al, Gastroenterology 2005
Wong et al, Aliment Pharmacol Ther 2003
Van Rossum et al, Gastroenterology 2008
Molecular markers
• DNA (genomic / metagenomic)
– SNPs, chromosomal aberration, microsatellite instability
– microbial markers
• RNA (transcriptomic)
– mRNA, micro-RNA
• Protein and metabolite
(proteomic / metabolomics)
– tumor antigens, metabolites
• Others
– epigenetic methylation
Types and clinical uses
RATIONALE
Using the microbiome as marker
CRC and microbiome
Enterotoxigenic Bacteroides fragilis
Wu S et al, Nat Med 2008 Goodwin et al, PNAS 2011
SPF Apc+/min
Enterotoxigenic
Genotoxic Escherichia coli
AOM il10-/- modelGenotoxic
Arthur et al, Science 2012
Fusobacterium nucleatum
Kostic et al, Cell Host Microbe 2013 Rubinstein et al, Cell Host Microbe 2013
Myeloid DC
Abed J et al, Cell Host Microbe 2016 Yang Y et al, Gastroenterology 2017
Fusobacterium nucleatum
• Enriched in cases
– Fusobacterium nucleatum
– Peptostreptococcus stomatis / anaerobius
– Parvimonas micra
– Solobacterium moorei
– Clostridium hathewayi
Yu, Gut 2015 Yu et al, Gut 2015
Oral pathogen network
Oral pathogens
Yu et al, Gut 2015
Nakatsu et al, Nat Commun 2015
CRC microbiota – cause or effect?
Wong et al, Gastroenterology 2017
Effects of CRC stools
Wong et al, Gastroenterology 2017
COLORECTAL CANCER
Using the microbiome as marker
Microbial marker panel
2.1 million microbial genes
140,455 genes associated with disease status
(p<0.01, FDR=11%)
20 genes identified by
mRMR feature selection method
CRC index of log
abundance
Yu et al, Gut 2015
Microbial marker panel
Classifier of 22 speciesAUC metagenome = 0.84AUC clinical score = 0.63
Zeller et al, Mol Syst Biol 2014
Microbial marker panel
Zackular JP et al, Cancer Prev Res 2014
Microbial marker panel
Liang et al, Clin Cancer Res 2016
Fusobacterium nucleatum (Fn)
• Relative abundance of
three bacteria in 309 +
181 subjects
• Three bacteria
including
Fusobacterium
nucleatum (Fn)
Wong et al, Gut 2017
Abundance in controls
and colorectal cancer patients
Performance of Fn marker
Wong et al, Gut 2017
Improve performance of FIT
Salvage missed tumors
• Combining FIT with Fn
increases its detection rates for
CRC to a sensitivity of 92.3%
• The combined test salvages
more than 75% of the CRC
samples missed by FIT alone
Fn as a marker for CRC
• Kostic et al, Cell Host Microbe 2013
• Wu et al, Microb Ecol 2013
• Anh et al, J Natl Cancer Inst 2013
• Zeller et al, Mol Syst Biol 2014
• Zackular et al, Cancer Prev Res 2014
• Flanagan et al, Eur J Clin Microbiol Infect Dis 2014
• Goedert et al, EBioMedicine 2015
• Yu et al, Gut 2015
• Shah et al, Gut 2016
• Liang et al, Clin Cancer Res 2016
• Wong et al, Gut 2017
• Suehiro et al, Ann Clin Biol 2017
• Ekolf et al, Int J Cancer 2017
Are we aiming right?
ADENOMA
Using the microbiome as marker
Can we use Fn for adenoma?
Kostic et al, Cell Host Microbe 2013 Zeller et al, Mol Syst Biol 2014
Fn marker for advanced adenoma
AUC - 0.56 (FIT), 0.59 (Fn)
0.65 (combined)
It’s a long way
http://www.molecularmedicineireland.ie/
We are here Hopeful, but need to look ahead
It is fruitful – FDA approved markers
Challenges with microbial markers
1. Challenges with the unknowns
Daily fluctuations
Food, antibiotics
Effects of diseases and drugs
Ethnic differences
2. Screening setting unknown
3. Feasibility and convenience in use
Thank you
• Cheong Chow
• Dr Thomas Kwong
• Dr Jessie Liang
• Professor Jun Yu
• Professor Joseph Sung