Microbiome as a marker for CRC screening

Transcription

1 WEO CRC Screening Committee Meeting 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

2 Global burden of CRC Incidence: 2 nd cancer in female (~ ) 3 rd cancer in male (~ ) Mortality: 4 th cancer (~ ) WHO 2015 and World Cancer Report 2014

3 Rationale of CRC screening APC / KRAS Smad2/4 p53 Up to 10 years can we catch it?

4 Screening reduces mortality Before screening After screening Jemal et al, Cancer J Clin 2008 Zauber et al, NEJM 2012

5 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

6 Fecal occult blood markers Guaiac fecal-occult blood test (gfobt) Detects heme Faecal immunochemical test (FIT) Specific antibodies to globin Limited by Limited sensitivity (37-79%) Imperfect specificity Need for dietary restriction Performance Sensitivity for CRC % Sensitivity for AN % 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

7 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

8 Types and clinical uses

9 Using the microbiome as marker RATIONALE

10 CRC and microbiome

11 Enterotoxigenic Bacteroides fragilis Enterotoxigenic SPF Apc +/min Wu S et al, Nat Med 2008 Goodwin et al, PNAS 2011

12 Genotoxic Escherichia coli Genotoxic AOM il10 -/- model Arthur et al, Science 2012

13 Fusobacterium nucleatum Myeloid DC Kostic et al, Cell Host Microbe 2013 Rubinstein et al, Cell Host Microbe 2013

14 Fusobacterium nucleatum Abed J et al, Cell Host Microbe 2016 Yang Y et al, Gastroenterology 2017

15 Enriched in cases Fusobacterium nucleatum Peptostreptococcus stomatis / anaerobius Parvimonas micra Solobacterium moorei Clostridium hathewayi Yu, Gut 2015 Yu et al, Gut 2015

16 Oral pathogen network Oral pathogens Yu et al, Gut 2015

17 Nakatsu et al, Nat Commun 2015

18 CRC microbiota cause or effect? Wong et al, Gastroenterology 2017

19 Effects of CRC stools Wong et al, Gastroenterology 2017

20 Using the microbiome as marker COLORECTAL CANCER

21 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

22 Microbial marker panel Classifier of 22 species AUC metagenome = 0.84 AUC clinical score = 0.63 Zeller et al, Mol Syst Biol 2014

23 Microbial marker panel Zackular JP et al, Cancer Prev Res 2014

24 Microbial marker panel Liang et al, Clin Cancer Res 2016

25 Fusobacterium nucleatum (Fn) Relative abundance of three bacteria in subjects Three bacteria including Fusobacterium nucleatum (Fn) Abundance in controls and colorectal cancer patients Wong et al, Gut 2017

26 Performance of Fn marker Improve performance of FIT Wong et al, Gut 2017

27 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

28 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?

29 Using the microbiome as marker ADENOMA

30 Can we use Fn for adenoma? Kostic et al, Cell Host Microbe 2013 Zeller et al, Mol Syst Biol 2014

31 Fn marker for advanced adenoma AUC (FIT), 0.59 (Fn) 0.65 (combined)

32 It s a long way We are here Hopeful, but need to look ahead

33 It is fruitful FDA approved markers

34 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

35 Thank you Cheong Chow Dr Thomas Kwong Dr Jessie Liang Professor Jun Yu Professor Joseph Sung