Analysis of the whole-exome sequencing of tumor and circulating tumor DNA in metastatic melanoma

Russell J. Diefenbach, Jenny H. Lee, Dario Strbenac, Jean Y. H. Yang, Alexander M. Menzies, Matteo S. Carlino, Georgina V. Long, Andrew J. Spillane, Jonathan R. Stretch, Robyn P. M. Saw, John F. Thompson, Sydney Ch'ng, Richard A. Scolyer, Richard F. Kefford, Helen Rizos

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    15 Citations (Scopus)
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    The use of circulating tumor DNA (ctDNA) to monitor cancer progression and response to therapy has significant potential but there is only limited data on whether this technique can detect the presence of low frequency subclones that may ultimately confer therapy resistance. In this study, we sought to evaluate whether whole-exome sequencing (WES) of ctDNA could accurately profile the mutation landscape of metastatic melanoma. We used WES to identify variants in matched, tumor-derived genomic DNA (gDNA) and plasma-derived ctDNA isolated from a cohort of 10 metastatic cutaneous melanoma patients. WES parameters such as sequencing coverage and total sequencing reads were comparable between gDNA and ctDNA. The mutant allele frequency of common single nucleotide variants was lower in ctDNA, reflecting the lower read depth and minor fraction of ctDNA within the total circulating free DNA pool. There was also variable concordance between gDNA and ctDNA based on the total number and identity of detected variants and this was independent of the tumor biopsy site. Nevertheless, established melanoma driver mutations and several other melanoma-associated mutations were concordant between matched gDNA and ctDNA. This study highlights that WES of ctDNA could capture clinically relevant mutations present in melanoma metastases and that enhanced sequencing sensitivity will be required to identify low frequency mutations.
    Original languageEnglish
    Article number1905
    Pages (from-to)1-14
    Number of pages14
    Issue number12
    Publication statusPublished - 29 Nov 2019

    Bibliographical note

    Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


    • whole exome sequencing
    • Melanoma
    • circulating tumour DNA


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