Population stratification with molecular biomarkers could improve the cost-benefit of lung cancer screening programmes and reduce false positives. We aim to establish that somatic copy number aberrations (SCNA) are detected in circulating cell-free DNA (cfDNA) of lung cancer cases. We hypothesise that the number and magnitude of SCNA might also serve as a discriminative test to aid early lung cancer detection.
Standard protocols were followed to process matched cfDNA and lymphocyte DNA for 51 untreated lung cancer cases, 30 high risk controls and 10 low risk controls. Low coverage DNA sequencing was carried out on the Illumina Hiseq 2500 and read copy number profiles were established with the software CNAnorm. A genomic instability score was evaluated by defining the area under the receiver operating characteristic curve (AUROC).
The median coverage of the genome for cfDNA was 0.49X (range 0.2X-0.63X). There was no significant difference between the median whole genome copy number aberration (CNA) score for early stage lung cancer and high risk controls, 398 (117-15373) vs 252 (149-7122) p = 0.25. The AUROC was 0.60 (95% CI 0.47-0.78) for early stage cancer (N = 21) and high risk controls compared to an AUROC of 0.74 (95% CI 0.63-0.85) for all lung cancer cases. The CNA score was a significant prognostic factor in univariable (HR 1.22 (95% CI 1.05-1.42 p = 0.008) but not multivariable analyses (HR 0.91 (95% CI 0.73-1.15 p = 0.45).
Our preliminary results demonstrate non-invasive detection of tumour derived copy number alterations with low coverage whole genome sequencing. The CNA score is not recommended as a stand-alone test to aid early lung cancer detection.
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Cancer Research UK and Yorkshire Cancer Research UK and The Roy Castle Foundation UK
All authors have declared no conflicts of interest.