Profiling of Circulating Free DNA Using Targeted and Genome-wide Sequencing in Patients with SCLC

Sumitra Mohan, Victoria Foy, Mahmood Ayub, Hui Sun Leong, Pieta Schofield, Sudhakar Sahoo, Tine Descamps, Bedirhan Kilerci, Nigel K. Smith, Mathew Carter, Lynsey Priest, Cong Zhou, T. Hedley Carr, Crispin Miller, Corinne Faivre-Finn, Fiona Blackhall, Dominic G. Rothwell, Caroline Dive, Ged Brady

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction
SCLC accounts for approximately 250,000 deaths worldwide each year. Acquisition of adequate tumor biopsy samples is challenging, and liquid biopsies present an alternative option for patient stratification and response monitoring.

Methods
We applied whole genome next-generation sequencing to circulating free DNA (cfDNA) from 39 patients with limited-stage (LS) SCLC and 30 patients with extensive-stage SCLC to establish genome-wide copy number aberrations and also performed targeted mutation analysis of 110 SCLC associated genes. Quantitative metrics were calculated for copy number aberrations, including percent genome amplified (PGA [the percentage of genomic regions amplified]), Z-score (a measure of standard deviation), and Moran’s I (a measure of spatial autocorrelation). In addition CellSearch, an epitope-dependent enrichment platform, was used to enumerate circulating tumor cells (CTCs) from a parallel blood sample.

Results
Genome-wide and targeted cfDNA sequencing data identified tumor-related changes in 94% of patients with LS SCLC and 100% of patients with extensive-stage SCLC. Parallel analysis of CTCs based on at least 1 CTC/7.5 mL of blood increased tumor detection frequencies to 95% for LS SCLC. Both CTC counts and cfDNA readouts correlated with disease stage and overall survival.

Conclusions
We demonstrate that a simple cfDNA genome-wide copy number approach provides an effective means of monitoring patients through treatment and show that targeted cfDNA sequencing identifies potential therapeutic targets in more than 50% of patients. We are now incorporating this approach into additional studies and trials of targeted therapies.
Original languageEnglish
Pages (from-to)216-230
Number of pages15
JournalJournal of Thoracic Oncology
Volume15
Issue number2
Early online date16 Oct 2019
DOIs
Publication statusPublished - 1 Feb 2020

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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