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Approved research

Monitoring tumour burden in circulating free DNA by low coverage whole genome sequencing

Principal Investigator: Dr Stefano Lise
Approved Research ID: 58864
Approval date: April 20th 2020

Lay summary

It has long been recognised that degraded DNA fragments freely circulate in the bloodstream. In cancer patients the level of circulating free DNA (cfDNA) is significantly increased and, importantly, contains also tumour derived DNA (circulating tumour DNA or ctDNA). As ctDNA is believed to be representative of the entire tumour genome, over the past decade the analysis of cfDNA has emerged as a highly promising and minimally invasive strategy in precision oncology. Studies have shown that the level of ctDNA correlates with disease course and it can be used for monitoring response to treatment in patients. In this project we aim to develop a method that can reliably detect and accurately quantify the tumour burden in sequential cfDNA samples using low coverage whole genome sequencing. To achieve the required sensitivity at low tumour concentrations we will rely on the availability of a patient's pre-treatment sample. Normal, healthy human cells typically comprise a set of 23 pairs of chromosomes. Cancer cells on the other hand often have abnormal numbers of chromosomes and/or deletion or duplication of large DNA regions. This feature can be exploited to determine and quantify the presence of tumour DNA in a sample. We will sequence a patient's healthy (germline) sample and reconstruct his/her full genomic profile by leveraging the vast amount of genetic data available at UK Biobank. From the sequencing of the pre-treatment sample and the reconstructed genomic profile we will identify and characterise patient specific chromosome abnormalities that will be tracked in follow up samples. Our approach will provide an alternative and complementary solution to currently available methods to detect tumour DNA in circulation. It will potentially extend the clinical applications of so-called 'liquid biopsies'. We plan to complete the project within 12 months.