Article Text

Download PDFPDF
Original research
Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers
  1. Peter Georgeson1,2,
  2. Bernard J Pope1,2,3,
  3. Christophe Rosty1,2,4,5,
  4. Mark Clendenning1,2,
  5. Khalid Mahmood1,2,3,
  6. Jihoon E Joo1,2,
  7. Romy Walker1,2,
  8. Ryan A Hutchinson1,2,
  9. Susan Preston1,2,
  10. Julia Como1,2,
  11. Sharelle Joseland1,2,
  12. Aung Ko Win6,7,
  13. Finlay A Macrae7,8,
  14. John L Hopper6,
  15. Dmitri Mouradov9,10,
  16. Peter Gibbs9,10,11,
  17. Oliver M Sieber9,10,12,13,
  18. Dylan E O'Sullivan14,15,
  19. Darren R Brenner14,15,16,
  20. Steve Gallinger17,18,19,
  21. Mark A Jenkins2,6,
  22. Ingrid M Winship7,20,
  23. Daniel D Buchanan1,2,7
  1. 1 Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia
  2. 2 University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia
  3. 3 Melbourne Bioinformatics, The University of Melbourne, Melbourne, Victoria, Australia
  4. 4 Envoi Pathology, Brisbane, Queensland, Australia
  5. 5 University of Queensland, School of Medicine, Herston, Queensland, Australia
  6. 6 Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Victoria, Australia
  7. 7 Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
  8. 8 Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
  9. 9 Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  10. 10 Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
  11. 11 Department of Medical Oncology, Western Health, Victoria, Australia
  12. 12 Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia
  13. 13 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
  14. 14 Department of Oncology, University of Calgary, Calgary, Alberta, Canada
  15. 15 Department of Community Health Sciences, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
  16. 16 Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, Alberta, Canada
  17. 17 Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, The University of Toronto, Toronto, Ontario, Canada
  18. 18 Ontario Institute for Cancer Research, Toronto, Ontario, Canada
  19. 19 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  20. 20 Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
  1. Correspondence to Dr Daniel D Buchanan, Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia; daniel.buchanan{at}


Objective Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers.

Design Whole-exome sequencing of formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers.

Results The combination of mutational signatures SBS18 and SBS36 contributing >30% of a CRC’s signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10-5), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99); however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls.

Conclusion Assessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.

  • colorectal cancer
  • colorectal cancer screening
  • tumour markers
  • mutations
  • molecular pathology

Data availability statement

Data are available upon reasonable request.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

Data are available upon reasonable request.

View Full Text


  • Twitter @dan_buchanan

  • Contributors DDB, PG, MC and IMW conceived the original study concept and design and designed the analysis. CR, FAM, IMW, AKW, JLH, MAJ, SG, DB, DOS, NM, PG, OMS, DM contributed to the acquisition of study data. The sample curation and laboratory testing was performed by MC, RW, RH, JEJ, SP, SJ, JC. PG, BJP, KM implemented the bioinformatics analysis pipeline. PG, DDB, BJP, MAJ designed and performed the statistical analyses. PG and DDB prepared the manuscript. All authors provided critical revisions to the manuscript for important intellectual content and have read and approved of the final manuscript.

  • Funding Funding by a National Health and Medical Research Council of Australia (NHMRC) project grant GNT1125269 (PI- Daniel Buchanan), supported the design, analysis and interpretation of data. PG is supported by an Australian Government Research Training Program Scholarship. DDB is supported by a NHMRC R.D. Wright Career Development Fellowship (GNT1125268) and funding from the University of Melbourne Research at Melbourne Accelerator Program (R@MAP). AKW is a NHMRC Career Development Fellow. MAJ is a NHMRC Senior Research Fellow. JLH is a NHMRC Senior Principal Research Fellow. O.M.S. is a NHMRC Senior Research Fellow (APP1136119). BJP is supported by a Victorian Health and Medical Research Fellowship. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number U01CA167551 and through a cooperative agreement with the Australasian Colorectal Cancer Family Registry (NCI/NIH U01 CA074778 and U01/U24 CA097735) and by the Victorian Cancer Registry, Australia and Ontario Familial Colorectal Cancer Registry (U01/U24 CA074783). This research was performed under CCFR approved projects C-AU-0818-01, C-AU-1014-02, C-AU-0312-01, C-AU-1013-02. DDB served as a consultant on the Tumour Agnostic (dMMR) Advisory Board of Merck Sharp and Dohme in 2017 and 2018 for Pembrolizumab.

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.