Whole-genome and transcriptome analysis enhances precision cancer treatment options

E Pleasance; A Bohm; L M Williamson; J M T Nelson; Y Shen; M Bonakdar; E Titmuss; V Csizmok; K Wee; S Hosseinzadeh; C J Grisdale; C Reisle; G A Taylor; E Lewis; M R Jones; D Bleile; S Sadeghi; W Zhang; A Davies; B Pellegrini; T Wong; R Bowlby; S K Chan; K L Mungall; E Chuah; A J Mungall; R A Moore; Y Zhao; B Deol; A Fisic; A Fok; D A Regier; D Weymann; D F Schaeffer; S Young; S Yip; K Schrader; N Levasseur; S K Taylor; X Feng; A Tinker; K J Savage; S Chia; K Gelmon; S Sun; H Lim; D J Renouf; S J M Jones; M A Marra; J Laskin

doi:10.1016/j.annonc.2022.05.522

Whole-genome and transcriptome analysis enhances precision cancer treatment options

Ann Oncol. 2022 Sep;33(9):939-949. doi: 10.1016/j.annonc.2022.05.522. Epub 2022 Jun 9.

Authors

E Pleasance¹, A Bohm², L M Williamson¹, J M T Nelson¹, Y Shen¹, M Bonakdar¹, E Titmuss¹, V Csizmok¹, K Wee¹, S Hosseinzadeh², C J Grisdale¹, C Reisle¹, G A Taylor¹, E Lewis¹, M R Jones¹, D Bleile¹, S Sadeghi¹, W Zhang¹, A Davies¹, B Pellegrini¹, T Wong¹, R Bowlby¹, S K Chan¹, K L Mungall¹, E Chuah¹, A J Mungall¹, R A Moore¹, Y Zhao¹, B Deol³, A Fisic³, A Fok¹, D A Regier⁴, D Weymann⁴, D F Schaeffer⁵, S Young⁶, S Yip⁶, K Schrader⁷, N Levasseur³, S K Taylor⁸, X Feng⁹, A Tinker³, K J Savage³, S Chia³, K Gelmon³, S Sun³, H Lim³, D J Renouf¹⁰, S J M Jones¹¹, M A Marra¹², J Laskin¹³

Affiliations

¹ Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver.
² Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver; Department of Medicine, University of British Columbia, Vancouver.
³ Department of Medical Oncology, BC Cancer, Vancouver.
⁴ Canadian Centre for Applied Research in Cancer Control, Cancer Control Research, BC Cancer, Vancouver.
⁵ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver; Pancreas Centre BC, Vancouver.
⁶ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver.
⁷ Hereditary Cancer Program, BC Cancer, Vancouver; Department of Medical Genetics, University of British Columbia, Vancouver.
⁸ Department of Medical Oncology, BC Cancer, Kelowna.
⁹ Department of Medical Oncology, BC Cancer, Victoria.
¹⁰ Department of Medical Oncology, BC Cancer, Vancouver; Pancreas Centre BC, Vancouver.
¹¹ Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver; Department of Medical Genetics, University of British Columbia, Vancouver; Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, Canada.
¹² Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver; Department of Medical Genetics, University of British Columbia, Vancouver.
¹³ Department of Medical Oncology, BC Cancer, Vancouver. Electronic address: jlaskin@bccancer.bc.ca.

PMID: 35691590
DOI: 10.1016/j.annonc.2022.05.522

Abstract

Background: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies.

Patients and methods: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected.

Results: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies.

Conclusions: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

Keywords: cancer genomics; chemotherapy; personalized medicine; targeted therapy; transcriptome sequencing; whole-genome sequencing.

Publication types

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

MeSH terms

Gene Expression Profiling
Genomics / methods
Humans
Mutation
Neoplasms* / drug therapy
Neoplasms* / genetics
Precision Medicine / methods
RNA
Transcriptome

Substances

RNA