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

• Published in: ESMO open Vol. 7; no. 4; p. 100540
• Main Authors: Ramarao-Milne, P., Kondrashova, O., Patch, A.-M., Nones, K., Koufariotis, L.T., Newell, F., Addala, V., Lakis, V., Holmes, O., Leonard, C., Wood, S., Xu, Q., Mukhopadhyay, P., Naeini, M.M., Steinfort, D., Williamson, J.P., Bint, M., Pahoff, C., Nguyen, P.T., Twaddell, S., Arnold, D., Grainge, C., Basirzadeh, F., Fielding, D., Dalley, A.J., Chittoory, H., Simpson, P.T., Aoude, L.G., Bonazzi, V.F., Patel, K., Barbour, A.P., Fennell, D.A., Robinson, B.W., Creaney, J., Hollway, G., Pearson, J.V., Waddell, N.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.08.2022; Elsevier
• Subjects: actionable mutations; cancer genomics; clinical genomics; microsatellite instability; Original Research; precision oncology; tumour mutation burden (TMB); whole-genome sequencing; microsatellite instability; precision oncology; clinical genomics; actionable mutations; whole-genome sequencing; cancer genomics; tumour mutation burden (TMB)
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1016/j.esmoop.2022.100540

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. 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. 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. 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. •Genome analysis revealed that treatment biomarkers are shared across solid tumours, highlighting repurposing opportunities.•Comprehensive panels detect most known biomarkers; however, WGS detects more biomarkers for treatments in clinical trials.•TMB is well correlated between sequencing methods, but absolute values vary and are dependent on mutation types considered.