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Analysis of the Whole-Exome Sequencing of Tumor and Circulating Tumor DNA in Metastatic Melanoma

1
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia
2
Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia
3
School of Mathematics and Statistics, The University of Sydney, Sydney, NSW 2006, Australia
4
Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia
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Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia
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Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW 2065, Australia
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Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, NSW 2145, Australia
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Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
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Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
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Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(12), 1905; https://doi.org/10.3390/cancers11121905
Received: 3 October 2019 / Revised: 31 October 2019 / Accepted: 26 November 2019 / Published: 29 November 2019
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. View Full-Text
Keywords: whole exome sequencing; melanoma; circulating tumor DNA whole exome sequencing; melanoma; circulating tumor DNA
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Diefenbach, R.J.; Lee, J.H.; Strbenac, D.; Yang, J.Y.H.; Menzies, A.M.; Carlino, M.S.; Long, G.V.; Spillane, A.J.; Stretch, J.R.; Saw, R.P.M.; Thompson, J.F.; Ch’ng, S.; Scolyer, R.A.; Kefford, R.F.; Rizos, H. Analysis of the Whole-Exome Sequencing of Tumor and Circulating Tumor DNA in Metastatic Melanoma. Cancers 2019, 11, 1905.

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