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Original article
Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer
  1. Jun Yu1†,
  2. Qiang Feng2,3†,
  3. Sunny Hei Wong1†,
  4. Dongya Zhang2†,
  5. Qiao yi Liang1†,
  6. Youwen Qin2,
  7. Longqing Tang2,
  8. Hui Zhao2,
  9. Jan Stenvang4,
  10. Yanli Li2,
  11. Xiaokai Wang2,
  12. Xiaoqiang Xu2,
  13. Ning Chen2,
  14. William Ka Kei Wu1,
  15. Jumana Al-Aama2,5,
  16. Hans Jørgen Nielsen6,
  17. Pia Kiilerich3,
  18. Benjamin Anderschou Holbech Jensen3,
  19. Tung On Yau1,
  20. Zhou Lan2,
  21. Huijue Jia2,
  22. Junhua Li2,
  23. Liang Xiao2,
  24. Thomas Yuen Tung Lam1,
  25. Siew Chien Ng1,
  26. Alfred Sze-Lok Cheng1,
  27. Vincent Wai-Sun Wong1,
  28. Francis Ka Leung Chan1,
  29. Xun Xu2,
  30. Huanming Yang2,
  31. Lise Madsen2,3,7,
  32. Christian Datz8,
  33. Herbert Tilg9,
  34. Jian Wang2,
  35. Nils Brünner2,4,
  36. Karsten Kristiansen2,3,
  37. Manimozhiyan Arumugam2,10,
  38. Joseph Jao-Yiu Sung1,
  39. Jun Wang2,3,5,11
  1. 1Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, LKS Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
  2. 2BGI-Shenzhen, Shenzhen, China
  3. 3Department of Biology, University of Copenhagen, Copenhagen, Denmark
  4. 4Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  5. 5Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
  6. 6Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark
  7. 7National Institute of Nutrition and Seafood Research, Bergen, Norway
  8. 8Department of Internal Medicine, Hospital Oberndorf, Q3 Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf, Austria
  9. 9First Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria
  10. 10The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  11. 11Macau University of Science and Technology, Macau, China
  1. Correspondence to Professor Jun Wang, Beijing Genomics Institute at Shenzhen, Shenzhen 518000, China; wangj{at}genomics.org.cn and Professor Joseph JY Sung, The Chinese University of Hong Kong, Hong Kong; jjysung{at}cuhk.edu.hk and Dr Manimozhiyan Arumugam, University of Copenhagen, 2200 Copenhagen, Denmark; arumugam{at}sund.ku.dk

Abstract

Objective To evaluate the potential for diagnosing colorectal cancer (CRC) from faecal metagenomes.

Design We performed metagenome-wide association studies on faecal samples from 74 patients with CRC and 54 controls from China, and validated the results in 16 patients and 24 controls from Denmark. We further validated the biomarkers in two published cohorts from France and Austria. Finally, we employed targeted quantitative PCR (qPCR) assays to evaluate diagnostic potential of selected biomarkers in an independent Chinese cohort of 47 patients and 109 controls.

Results Besides confirming known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with CRC, we found significant associations with several species, including Parvimonas micra and Solobacterium moorei. We identified 20 microbial gene markers that differentiated CRC and control microbiomes, and validated 4 markers in the Danish cohort. In the French and Austrian cohorts, these four genes distinguished CRC metagenomes from controls with areas under the receiver-operating curve (AUC) of 0.72 and 0.77, respectively. qPCR measurements of two of these genes accurately classified patients with CRC in the independent Chinese cohort with AUC=0.84 and OR of 23. These genes were enriched in early-stage (I–II) patient microbiomes, highlighting the potential for using faecal metagenomic biomarkers for early diagnosis of CRC.

Conclusions We present the first metagenomic profiling study of CRC faecal microbiomes to discover and validate microbial biomarkers in ethnically different cohorts, and to independently validate selected biomarkers using an affordable clinically relevant technology. Our study thus takes a step further towards affordable non-invasive early diagnostic biomarkers for CRC from faecal samples.

  • BACTERIAL INTERACTIONS
  • COLONIC MICROFLORA
  • COLORECTAL CANCER

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Footnotes

  • JuY, QF, SHW, DZ, QL contributed equally.

  • Correction notice This article has been corrected since it published Online First. The data sharing statement has been corrected.

  • Contributors JuY, QF, SHW, DZ and QL contributed equally. The project was designed by JuW, JoJS, JuY, NB and MA. JuY, QF, JoJS and JuW managed the project. JuY, TOY, JS, HJN, TYTL, SCN, QL, ASLC, VW-SW, WKKW and FKLC contributed to acquisition of clinical samples, patients’ information and clinical data analyses. QL, SHW, JuY, ZL, PK and BAHJ performed DNA experiments. JuW, JuY, SHW, MA, KK, QF and DYZ designed the analysis. DYZ, MA, QF, YWQ, LQT, YLL, YL, NC, HJJ, JHL, LX and ZL performed the data analysis. DYZ, MA, QF, YWQ, LQT, YLL, YL, NC, HJJ, JHL, LX and ZL worked on metagenomic-wide association study. QL, JuY and T OY did the experimental validation. MA, JuY, SH W, QF, DY Z and LQT wrote the paper. JuW, KK, LM, JoJS, JuY, NB, JiW, HMY, HJJ, JA-A and XX revised the paper.

  • Funding The project was supported by the National Basic Research Program of China (973 Program, 2011CB809203, 2013CB531401), SHHO foundation Hong Kong, theme-based Research Scheme of the Hong Kong Research Grants Council (T12-403-11), the introduction of innovative R&D team programme of Guangdong Province (no. 2009010016), the Danish Cancer Society (R72-A4659-13-S2) and the Shenzhen Municipal Government of China (CXB201108250098A).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Joint Chinese University of Hong Kong – New Territories East Cluster Clinical Research Ethics Committee (CUHK-NTEC CREC), Ethics Committee of the Capital Region of Denmark and Danish Data Protection Agency.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Metagenomic sequence data set has been deposited in European Nucleotide Archive with accession number PRJEB10878.

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