Oncomicrobial Community Profiling Identifies Clinicomolecular and Prognostic Subtypes of Colorectal Cancer

Dmitri Mouradov; Paul Greenfield; Shan Li; Eun-Jung In; Claire Storey; Anuratha Sakthianandeswaren; Peter Georgeson; Daniel D Buchanan; Robyn L Ward; Nicholas J Hawkins; Iain Skinner; Ian T Jones; Peter Gibbs; Chenkai Ma; Yi Jin Liew; Kim Y C Fung; Oliver M Sieber

doi:10.1053/j.gastro.2023.03.205

Oncomicrobial Community Profiling Identifies Clinicomolecular and Prognostic Subtypes of Colorectal Cancer

Gastroenterology. 2023 Jul;165(1):104-120. doi: 10.1053/j.gastro.2023.03.205. Epub 2023 Mar 16.

Authors

Dmitri Mouradov¹, Paul Greenfield², Shan Li³, Eun-Jung In¹, Claire Storey³, Anuratha Sakthianandeswaren¹, Peter Georgeson⁴, Daniel D Buchanan⁵, Robyn L Ward⁶, Nicholas J Hawkins⁷, Iain Skinner⁸, Ian T Jones⁹, Peter Gibbs¹⁰, Chenkai Ma¹¹, Yi Jin Liew¹¹, Kim Y C Fung¹¹, Oliver M Sieber¹²

Affiliations

¹ Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
² Energy Business Unit, Commonwealth Scientific and Industrial Research Organization, Lindfield, New South Wales, Australia; School of Natural Sciences, Macquarie University, North Ryde, New South Wales, Australia.
³ Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
⁴ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia; University of Melbourne Center for Cancer Research, Victorian Comprehensive Cancer Center, Melbourne, Victoria, Australia.
⁵ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia; University of Melbourne Center for Cancer Research, Victorian Comprehensive Cancer Center, Melbourne, Victoria, Australia; Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁶ Prince of Wales Clinical School and Lowy Cancer Research Center, UNSW Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
⁷ School of Medical Sciences, UNSW Sydney, Sydney, New South Wales, Australia.
⁸ Department of Surgery, Western Health, Footscray, Victoria, Australia.
⁹ Department of Surgery, Royal Melbourne Hospital, Parkville, Victoria, Australia.
¹⁰ Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia; Department of Medical Oncology, Western Health, St Albans, Victoria, Australia; Department of Medical Oncology, Western Health, Footscray, Victoria, Australia.
¹¹ Molecular Diagnostics Solutions, Commonwealth Scientific and Industrial Research Organization Health and Biosecurity, Westmead, New South Wales, Australia.
¹² Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia; Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia. Electronic address: sieber.o@wehi.edu.au.

PMID: 36933623
DOI: 10.1053/j.gastro.2023.03.205

Abstract

Background & aims: Dysbiosis of gut microbiota is linked to the development of colorectal cancer (CRC). However, microbiota-based stratification of CRC tissue and how this relates to clinicomolecular characteristics and prognosis remains to be clarified.

Methods: Tumor and normal mucosa from 423 patients with stage I to IV CRC were profiled by bacterial 16S rRNA gene sequencing. Tumors were characterized for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), APC, BRAF, KRAS, PIK3CA, FBXW7, SMAD4, and TP53 mutations, subsets for chromosome instability (CIN), mutation signatures, and consensus molecular subtypes (CMS). Microbial clusters were validated in an independent cohort of 293 stage II/III tumors.

Results: Tumors reproducibly stratified into 3 oncomicrobial community subtypes (OCSs) with distinguishing features: OCS1 (Fusobacterium/oral pathogens, proteolytic, 21%), right-sided, high-grade, MSI-high, CIMP-positive, CMS1, BRAF V600E, and FBXW7 mutated; OCS2 (Firmicutes/Bacteroidetes, saccharolytic, 44%), and OCS3 (Escherichia/Pseudescherichia/Shigella, fatty acid β-oxidation, 35%) both left-sided and exhibiting CIN. OCS1 was associated with MSI-related mutation signatures (SBS15, SBS20, ID2, and ID7) and OCS2 and OCS3 with SBS18 related to damage by reactive oxygen species. Among stage II/III patients, OCS1 and OCS3 both had poorer overall survival compared with OCS2 for microsatellite stable tumors (multivariate hazard ratio [HR], 1.85; 95% confidence interval [CI], 1.15-2.99; P = .012; and HR, 1.52; 95% CI 1.01-2.29; P = .044, respectively) and left-sided tumors (multivariate HR, 2.66; 95% CI, 1.45-4.86; P = .002; and HR, 1.76; 95% CI, 1.03-3.02; P = .039, respectively).

Conclusions: OCS classification stratified CRCs into 3 distinct subgroups with different clinicomolecular features and outcomes. Our findings provide a framework for a microbiota-based stratification of CRC to refine prognostication and to inform the development of microbiota-targeted interventions.

Keywords: Clinicomolecular Subtypes; Colorectal Cancer; Microbiota Classification; Prognosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chromosomal Instability
Colorectal Neoplasms* / pathology
CpG Islands
DNA Methylation
F-Box-WD Repeat-Containing Protein 7 / genetics
Humans
Microsatellite Instability
Mutation
Phenotype
Prognosis
Proto-Oncogene Proteins B-raf* / genetics
RNA, Ribosomal, 16S

Substances

F-Box-WD Repeat-Containing Protein 7
Proto-Oncogene Proteins B-raf
RNA, Ribosomal, 16S