Abstract
Circulating tumour DNA (ctDNA) allows tracking of the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. However, exploiting ctDNA to determine how a patient’s cancer is evolving in order to aid clinical decisions remains difficult. This is because ctDNA is a mix of fragmented alleles, and the contribution of different cancer deposits to ctDNA is largely unknown. Profiling ctDNA almost invariably requires prior knowledge of what genomic alterations to track. Here, we leverage on a rapid autopsy programme to demonstrate that unbiased genomic characterisation of several metastatic sites and concomitant ctDNA profiling at whole-genome resolution reveals the extent to which ctDNA is representative of widespread disease. We also present a methylation profiling method that allows tracking evolutionary changes in ctDNA at single-molecule resolution without prior knowledge. These results have critical implications for the use of liquid biopsies to monitor cancer evolution in humans and guide treatment.
Highlights
Circulating tumour DNA allows tracking of the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies
We developed a new methylation profiling approach applied to Circulating tumour DNA (ctDNA) that allows tracking the evolution of subpopulations of cancer cells in plasma at single-molecule resolution without prior knowledge of the mutational profiles of solid metastases
In this study we present the analysis of the metastatic cascade and ctDNA profile of LEGACY patients 1 and 2
Summary
Circulating tumour DNA (ctDNA) allows tracking of the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. Exploiting ctDNA to determine how a patient’s cancer is evolving in order to aid clinical decisions remains difficult. We present a methylation profiling method that allows tracking evolutionary changes in ctDNA at single-molecule resolution without prior knowledge. These results have critical implications for the use of liquid biopsies to monitor cancer evolution in humans and guide treatment. Liquid biopsies, comprising profiling circulating tumour DNA (ctDNA) from the plasma of cancer patients, have changed the way in which we can study human malignancies[1]. (c) The extent to which ctDNA reflects different metastatic lesions in distinct regions of the body remains largely unknown
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