Genome-Wide Analysis of Circulating Cell-Free DNA Copy Number Detects Active Melanoma and Predicts Survival

Shobha Silva, Sarah Danson, Dawn Teare, Fiona Taylor, James Bradford, Andrew J.g. Mcdonagh, Abdulazeez Salawu, Greg Wells, George J. Burghel, Ian Brock, Daniel Connley, Helen Cramp, David Hughes, Nick Tiffin, Angela Cox

Research output: Contribution to journalArticlepeer-review


BACKGROUND: A substantial number of melanoma patients develop local or metastatic recurrence, and early detection of these is vital to maximise benefit from new therapies such as inhibitors of BRAF and MEK, or immune checkpoints. This study explored the use of novel DNA copy-number profiles in circulating cell-free DNA (cfDNA) as a potential biomarker of active disease and survival.

PATIENTS AND METHODS: Melanoma patients were recruited from oncology and dermatology clinics in Sheffield, UK, and cfDNA was isolated from stored blood plasma. Using low-coverage whole-genome sequencing, we created copy-number profiles from cfDNA from 83 melanoma patients, 44 of whom had active disease. We used scoring algorithms to summarize copy-number aberrations and investigated their utility in multivariable logistic and Cox regression analyses.

RESULTS: The copy-number aberration score (CNAS) was a good discriminator of active disease (odds ratio, 3.1; 95% CI, 1.5–6.2; P = 0.002), and CNAS above or below the 75th percentile remained a significant discriminator in multivariable analysis for active disease (P = 0.019, with area under ROC curve of 0.90). Additionally, mortality was higher in those with CNASs above the 75th percentile than in those with lower scores (HR, 3.4; 95% CI, 1.5–7.9; P = 0.005), adjusting for stage of disease, disease status (active or resected), BRAF status, and cfDNA concentration.

CONCLUSIONS: This study demonstrates the potential of a de novo approach utilizing copy-number profiling of cfDNA as a biomarker of active disease and survival in melanoma. Longitudinal analysis of copy-number profiles as an early marker of relapsed disease is warranted.
Original languageEnglish
Pages (from-to)1338-1346
Number of pages9
JournalClinical Chemistry
Issue number9
Early online date28 Aug 2018
Publication statusPublished - 1 Sept 2018


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