Abstract
Through the delivery of large international projects including ICGC and TCGA, knowledge of cancer genomics is reaching saturation point. Enabling this to improve patient outcomes now requires embedding comprehensive genomic profiling into routine oncology practice. Towards this goal, this study defined the biologically and clinically relevant genomic features of adult cancer through detailed curation and analysis of large genomic datasets, accumulated literature and biomarker-driven therapeutics in clinic and development. The characteristics and prevalence of these features were then interrogated in 2348 whole genome sequences, covering 21 solid tumour types, generated by the PCAWG project. This analysis highlights the predominant contribution of copy number alterations and identifies a critical role for disruptive structural variants in the inactivation of clinically important tumour suppressor genes, including PTEN and RB1, which are not currently captured by diagnostic assays. This study defines a set of essential genomic features for the characterisation of common adult cancers.
Highlights
Substantial knowledge has accumulated around the genomic aberrations that underpin the development and progression of cancer, through the concerted efforts of large worldwide collaborations including the International Cancer Genome Consortium (ICGC), The Cancer Genome Atlas (TCGA) and, most recently, the PanCancer Analysis of Whole Genomes (PCAWG) [2,14,16]
While this model achieves dramatic responses for some patients, there is growing appreciation that a different approach is required to unlock the full potential of precision medicine, in order to help a wider range of cancer patients and to pre vent the often rapid acquisition of resistance to targeted therapies [3]
A range of sequencing-based cancer diagnostics are currently avail able from commercial and healthcare providers. These assays commonly report information for 400–500 genes. While this is broadly consistent with estimates of the total number of genes that play a biological role in cancer [15,16,23], analysis of the overlap in content between eight high-profile providers reveals poor correlation, with less than 15% of genes included in all tests, and over half of the genes present in only 1 or 2 assays (Fig. 1)
Summary
Substantial knowledge has accumulated around the genomic aberrations that underpin the development and progression of cancer, through the concerted efforts of large worldwide collaborations including the International Cancer Genome Consortium (ICGC), The Cancer Genome Atlas (TCGA) and, most recently, the PanCancer Analysis of Whole Genomes (PCAWG) [2,14,16]. Our current level of knowledge, is sufficient to define the vast majority of the clinically and biologically relevant cancer genomic space with a high degree of certainty Whilst this lexicon of cancer variants is close to completion, genomic profiling has yet to deliver on its potential for improving outcomes for cancer patients [17]. Advances to date have largely been based on a single gene - single drug paradigm delivered through a limited genomic test (a ‘companion diagnostic’), as exemplified by EGFR inhibitor ther apy for EGFR-mutant lung cancers While this model achieves dramatic responses for some patients, there is growing appreciation that a different approach is required to unlock the full potential of precision medicine, in order to help a wider range of cancer patients and to pre vent the often rapid acquisition of resistance to targeted therapies [3]
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