Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers

P Georgeson; BJ Pope; C Rosty; M Clendenning; K Mahmood; JE Joo; R Walker; RA Hutchinson; S Preston; J Como; S Joseland; AK Win; FA Macrae; JL Hopper; D Mouradov; P Gibbs; OM Sieber; DE O'Sullivan; DR Brenner; S Gallinger; MA Jenkins; IM Winship; DD Buchanan

Journal article

Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers

P Georgeson, BJ Pope, C Rosty, M Clendenning, K Mahmood, JE Joo, R Walker, RA Hutchinson, S Preston, J Como, S Joseland, AK Win, FA Macrae, JL Hopper, D Mouradov, P Gibbs, OM Sieber, DE O'Sullivan, DR Brenner, S Gallinger Show all

Gut | BMJ PUBLISHING GROUP | Published : 2021

DOI: 10.1136/gutjnl-2019-320462

Abstract

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 in..

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University of Melbourne Researchers

Peter Georgeson Author

Bernard Pope Author

Christophe Rosty Author

Mark Clendenning Author

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Funding Acknowledgements

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.