Abstract
Somatic alterations to the genomes of solid tumours, which in some cases represent actionable drivers, provide diagnostic and prognostic insight into these complex diseases. Spatial and longitudinal tracking of somatic genomic alterations (SGAs) in patient tumours has emerged as a new avenue of investigation, not only as a disease monitoring strategy, but also to improve our understanding of heterogeneity and clonal evolution from diagnosis through disease progression. Furthermore, analysis of circulating-free DNA (cfDNA) in the so-called “liquid biopsy” has emerged as a non-invasive method to identify genomic information to inform targeted therapy and may also capture the heterogeneity of the primary and metastatic tumours. Considering the potential of cfDNA analysis as a translational laboratory tool in clinical practice, establishing the extent to which cfDNA represents the SGAs of tumours, particularly actionable driver alterations, becomes a matter of importance, warranting standardisation of methods and practices. Here, we assess the utilisation of cfDNA for molecular profiling of SGAs in tumour tissue across a broad range of solid tumours. Moreover, we examine the underlying factors contributing to discordance of detected SGAs between cfDNA and tumour tissue.
Highlights
Cancer genomes display a plethora of somatic genomic alterations (SGAs), including single nucleotide variations (SNVs), insertions and deletions, focal amplifications, gene fusions, copy number alterations (CNAs) and numerical and segmental chromosomal alterations
Discordance observed between circulating-free DNA (cfDNA) and tumour tissue may be due to the subclonal presentation of drivers in the tumour in later stages of the disease, which can affect the detectability of these drivers in cfDNA and impact concordance rates [86]
This study revealed chromosome arm gains and losses, high level copy number gains, fusions and SNVs indicated in the pathogenesis of prostate cancer, the timely and costly deep coverage whole genome sequencing (WGS) may be avoidable
Summary
Cancer genomes display a plethora of somatic genomic alterations (SGAs), including single nucleotide variations (SNVs), insertions and deletions (indels), focal amplifications, gene fusions, copy number alterations (CNAs) and numerical and segmental chromosomal alterations (NCAs and SCAs). García-Foncillas et al, in a study of metastatic colorectal cancer, report that when SGAs (such as RAS mutations) of cfDNA and liver metastasis were compared, a higher concordance rate was obtained than that of cfDNA and lung metastasis [65] This observation was explained by the higher vascularisation of liver tissue and the greater likelihood of DNA release into the circulation [66]. Xie et al, tested 35 pairs of NSCLC primary tumour tissues or metastatic tumours and plasma from treatment-naïve patients using targeted sequencing for a custom panel of 56 lung cancer genes They interrogated similarities between primary and metastatic tumours and matching cfDNA and observed 62% concordance between the trio (67/108 mutations identified). Studies using cfDNA that investigated (1) the mechanism of resistance to drug therapy and (2) the comparison of methods and (3) efficacy of drug therapy have not been included, but studies that compare the extent of which cfDNA and reflect driver and actionable driver alterations of the tumours, primary and metastatic have been included
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