Pan-cancer whole-genome analyses of metastatic solid tumours

Peter Priestley, Jonathan Baber, Martijn P. Lolkema, Neeltje Steeghs, Ewart Bruijn, Charles Shale, Korneel Duyvesteyn, Susan Haidari, Arne Hoeck, Wendy Onstenk, Paul Roepman, Mircea Voda, Haiko J. Bloemendal, Vivianne C. G. Tjan-Heijnen, Carla M. L. Herpen, Mariette Labots, Petronella O. Witteveen, Egbert F. Smit, Stefan Sleijfer, Emile E. Voest and Edwin Cuppen ()
Additional contact information
Peter Priestley: Hartwig Medical Foundation
Jonathan Baber: Hartwig Medical Foundation
Martijn P. Lolkema: Center for Personalized Cancer Treatment
Neeltje Steeghs: Center for Personalized Cancer Treatment
Ewart Bruijn: Hartwig Medical Foundation
Charles Shale: Hartwig Medical Foundation Australia
Korneel Duyvesteyn: Hartwig Medical Foundation
Susan Haidari: Hartwig Medical Foundation
Arne Hoeck: University Medical Center Utrecht
Wendy Onstenk: Hartwig Medical Foundation
Paul Roepman: Hartwig Medical Foundation
Mircea Voda: Hartwig Medical Foundation
Haiko J. Bloemendal: Meander Medisch Centrum
Vivianne C. G. Tjan-Heijnen: Maastricht University Medical Center
Carla M. L. Herpen: Radboud University Medical Center
Mariette Labots: VU Medical Center
Petronella O. Witteveen: University Medical Center Utrecht
Egbert F. Smit: Center for Personalized Cancer Treatment
Stefan Sleijfer: Center for Personalized Cancer Treatment
Emile E. Voest: Center for Personalized Cancer Treatment
Edwin Cuppen: Hartwig Medical Foundation

Nature, 2019, vol. 575, issue 7781, 210-216

Abstract: Abstract Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.

Date: 2019
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DOI: 10.1038/s41586-019-1689-y

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