Comparison of actionable events detected in cancer genomes by whole-genome sequencing, in silico whole-exome and mutation panels

P Ramarao-Milne; O Kondrashova; A-M Patch; K Nones; L T Koufariotis; F Newell; V Addala; V Lakis; O Holmes; C Leonard; S Wood; Q Xu; P Mukhopadhyay; M M Naeini; D Steinfort; J P Williamson; M Bint; C Pahoff; P T Nguyen; S Twaddell; D Arnold; C Grainge; F Basirzadeh; D Fielding; A J Dalley; H Chittoory; P T Simpson; L G Aoude; V F Bonazzi; K Patel; A P Barbour; D A Fennell; B W Robinson; J Creaney; G Hollway; J V Pearson; N Waddell

doi:10.1016/j.esmoop.2022.100540

Comparison of actionable events detected in cancer genomes by whole-genome sequencing, in silico whole-exome and mutation panels

ESMO Open. 2022 Aug;7(4):100540. doi: 10.1016/j.esmoop.2022.100540. Epub 2022 Jul 15.

Authors

P Ramarao-Milne¹, O Kondrashova², A-M Patch², K Nones², L T Koufariotis², F Newell², V Addala², V Lakis², O Holmes², C Leonard², S Wood², Q Xu², P Mukhopadhyay², M M Naeini², D Steinfort³, J P Williamson⁴, M Bint⁵, C Pahoff⁶, P T Nguyen⁷, S Twaddell⁸, D Arnold⁸, C Grainge⁸, F Basirzadeh⁹, D Fielding⁹, A J Dalley¹⁰, H Chittoory¹⁰, P T Simpson¹⁰, L G Aoude¹¹, V F Bonazzi¹¹, K Patel¹¹, A P Barbour¹², D A Fennell¹³, B W Robinson¹⁴, J Creaney¹⁴, G Hollway², J V Pearson², N Waddell¹⁵

Affiliations

¹ Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Australian e-Health Research Centre, Commonwealth Scientific and Industrial Research Organisation, Brisbane, Australia.
² Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
³ Department of Thoracic Medicine, Royal Melbourne Hospital, Melbourne, Australia.
⁴ Department of Thoracic Medicine, Liverpool Hospital Sydney, Sydney, Australia.
⁵ Department of Thoracic Medicine, Sunshine Coast University Hospital, Birtinya, Australia.
⁶ Department of Respiratory Medicine, Gold Coast University Hospital, Southport, Australia.
⁷ Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia.
⁸ Department of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, Australia.
⁹ Department of Thoracic Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia.
¹⁰ UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia.
¹¹ The University of Queensland Diamantina Institute, Faculty of Medicine, University of Queensland, Brisbane, Australia.
¹² The University of Queensland Diamantina Institute, Faculty of Medicine, University of Queensland, Brisbane, Australia; Upper Gastro-intestinal Surgical Unit, Department of Surgery, Princess Alexandra Hospital, Brisbane, Australia.
¹³ Cancer Research UK Centre Leicester, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, UK.
¹⁴ National Centre for Asbestos Related Disease, Institute of Respiratory Health, University of Western Australia, Nedlands, Australia; Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia.
¹⁵ Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia. Electronic address: [email protected].

Abstract

Background: Next-generation sequencing is used in cancer research to identify somatic and germline mutations, which can predict sensitivity or resistance to therapies, and may be a useful tool to reveal drug repurposing opportunities between tumour types. Multigene panels are used in clinical practice for detecting targetable mutations. However, the value of clinical whole-exome sequencing (WES) and whole-genome sequencing (WGS) for cancer care is less defined, specifically as the majority of variants found using these technologies are of uncertain significance.

Patients and methods: We used the Cancer Genome Interpreter and WGS in 726 tumours spanning 10 cancer types to identify drug repurposing opportunities. We compare the ability of WGS to detect actionable variants, tumour mutation burden (TMB) and microsatellite instability (MSI) by using in silico down-sampled data to mimic WES, a comprehensive sequencing panel and a hotspot mutation panel.

Results: We reveal drug repurposing opportunities as numerous biomarkers are shared across many solid tumour types. Comprehensive panels identify the majority of approved actionable mutations, with WGS detecting more candidate actionable mutations for biomarkers currently in clinical trials. Moreover, estimated values for TMB and MSI vary when calculated from WGS, WES and panel data, and are dependent on whether all mutations or only non-synonymous mutations were used. Our results suggest that TMB and MSI thresholds should not only be tumour-dependent, but also be sequencing platform-dependent.

Conclusions: There is a large opportunity to repurpose cancer drugs, and these data suggest that comprehensive sequencing is an invaluable source of information to guide clinical decisions by facilitating precision medicine and may provide a wealth of information for future studies. Furthermore, the sequencing and analysis approach used to estimate TMB may have clinical implications if a hard threshold is used to indicate which patients may respond to immunotherapy.

Keywords: actionable mutations; cancer genomics; clinical genomics; microsatellite instability; precision oncology; tumour mutation burden (TMB); whole-genome sequencing.

Publication types

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

MeSH terms

Biomarkers, Tumor
Exome Sequencing
Exome*
High-Throughput Nucleotide Sequencing
Humans
Microsatellite Instability
Mutation
Neoplasms*

Substances

Biomarkers, Tumor