Pan-cancer whole-genome analyses of metastatic solid tumours
By P. Priestley, Jonathan Baber, M. Lolkema, N. Steeghs, Ewart de Bruijn, C. Shale, Korneel Duyvesteyn, S. Haidari, A. van Hoeck, W. Onstenk and 11 more. Nature, 2019
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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. The mutational landscape of metastatic cancer genomes is analysed in a large-scale, pan-cancer study of metastatic solid tumours that includes whole-genome sequencing of 2,520 tumour–normal tissue pairs.
Subfields: Cancer Research, Pathology and Forensic Medicine, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/61973da18e9bbaaae94682c760f73b5a02ecffb5
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Citations in the corpus
- Molecular profiling for precision cancer therapies (2020, methodology): “The second cohort in microsatellite stable colorectal cancer with TMB between 11 and 22 mutations per megabase showed limited clinical benefit, leading to the closure of the arm [39, 167, 172].”
- Harnessing multimodal data integration to advance precision oncology (2021, background): “Higher-order genomic properties such as tumour mutational burden (TMB) 53 , endogenous mutational processes such as MSI 54 and homologous recombination deficiency (HRD), and large-scale features such as whole genome duplication 55 are also clinically meaningful.”