Locus-specific concordance of genomic alterations between tissue and plasma circulating tumor DNA in metastatic melanoma

Leslie Calapre, Tindaro Giardina, Cleo Robinson, Anna L Reid, Zeyad Al-Ogaili, Michelle R Pereira, Ashleigh C McEvoy, Lydia Warburton, Nicholas K Hayward, Muhammad A Khattak, Tarek M Meniawy, Michael Millward, Benhur Amanuel, Melanie Ziman, Elin S Gray

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Abstract

Circulating tumor DNA (ctDNA) may serve as a surrogate to tissue biopsy for noninvasive identification of mutations across multiple genetic loci and for disease monitoring in melanoma. In this study, we compared the mutation profiles of tumor biopsies and plasma ctDNA from metastatic melanoma patients using custom sequencing panels targeting 30 melanoma-associated genes. Somatic mutations were identified in 20 of 24 melanoma biopsies, and 16 of 20 (70%) matched-patient plasmas had detectable ctDNA. In a subgroup of seven patients for whom matching tumor tissue and plasma were sequenced, 80% of the mutations found in tumor tissue were also detected in ctDNA. However, TERT promoter mutations were only detected by ddPCR, and promoter mutations were consistently found at lower concentrations than other driver mutations in longitudinal samples. In vitro experiments revealed that mutations in promoter regions of TERT and DPH3 are underrepresented in ctDNA. While the results underscore the utility of using ctDNA as an alternative to tissue biopsy for genetic profiling and surveillance of the disease, our study highlights the underrepresentation of promoter mutations in ctDNA and its potential impact on quantitative liquid biopsy applications.

Original languageEnglish
Pages (from-to)171-184
Number of pages14
JournalMolecular Oncology
Early online date12 Oct 2018
DOIs
Publication statusPublished - Feb 2019

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Melanoma
DNA
Mutation
Neoplasms
Biopsy
Inborn Genetic Diseases
Genetic Loci
Genetic Promoter Regions
Genes

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Calapre, Leslie ; Giardina, Tindaro ; Robinson, Cleo ; Reid, Anna L ; Al-Ogaili, Zeyad ; Pereira, Michelle R ; McEvoy, Ashleigh C ; Warburton, Lydia ; Hayward, Nicholas K ; Khattak, Muhammad A ; Meniawy, Tarek M ; Millward, Michael ; Amanuel, Benhur ; Ziman, Melanie ; Gray, Elin S. / Locus-specific concordance of genomic alterations between tissue and plasma circulating tumor DNA in metastatic melanoma. In: Molecular Oncology. 2019 ; pp. 171-184.
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title = "Locus-specific concordance of genomic alterations between tissue and plasma circulating tumor DNA in metastatic melanoma",
abstract = "Circulating tumor DNA (ctDNA) may serve as a surrogate to tissue biopsy for noninvasive identification of mutations across multiple genetic loci and for disease monitoring in melanoma. In this study, we compared the mutation profiles of tumor biopsies and plasma ctDNA from metastatic melanoma patients using custom sequencing panels targeting 30 melanoma-associated genes. Somatic mutations were identified in 20 of 24 melanoma biopsies, and 16 of 20 (70{\%}) matched-patient plasmas had detectable ctDNA. In a subgroup of seven patients for whom matching tumor tissue and plasma were sequenced, 80{\%} of the mutations found in tumor tissue were also detected in ctDNA. However, TERT promoter mutations were only detected by ddPCR, and promoter mutations were consistently found at lower concentrations than other driver mutations in longitudinal samples. In vitro experiments revealed that mutations in promoter regions of TERT and DPH3 are underrepresented in ctDNA. While the results underscore the utility of using ctDNA as an alternative to tissue biopsy for genetic profiling and surveillance of the disease, our study highlights the underrepresentation of promoter mutations in ctDNA and its potential impact on quantitative liquid biopsy applications.",
author = "Leslie Calapre and Tindaro Giardina and Cleo Robinson and Reid, {Anna L} and Zeyad Al-Ogaili and Pereira, {Michelle R} and McEvoy, {Ashleigh C} and Lydia Warburton and Hayward, {Nicholas K} and Khattak, {Muhammad A} and Meniawy, {Tarek M} and Michael Millward and Benhur Amanuel and Melanie Ziman and Gray, {Elin S}",
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Calapre, L, Giardina, T, Robinson, C, Reid, AL, Al-Ogaili, Z, Pereira, MR, McEvoy, AC, Warburton, L, Hayward, NK, Khattak, MA, Meniawy, TM, Millward, M, Amanuel, B, Ziman, M & Gray, ES 2019, 'Locus-specific concordance of genomic alterations between tissue and plasma circulating tumor DNA in metastatic melanoma' Molecular Oncology, pp. 171-184. https://doi.org/10.1002/1878-0261.12391

Locus-specific concordance of genomic alterations between tissue and plasma circulating tumor DNA in metastatic melanoma. / Calapre, Leslie; Giardina, Tindaro; Robinson, Cleo; Reid, Anna L; Al-Ogaili, Zeyad; Pereira, Michelle R; McEvoy, Ashleigh C; Warburton, Lydia; Hayward, Nicholas K; Khattak, Muhammad A; Meniawy, Tarek M; Millward, Michael; Amanuel, Benhur; Ziman, Melanie; Gray, Elin S.

In: Molecular Oncology, 02.2019, p. 171-184.

Research output: Contribution to journalArticle

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T1 - Locus-specific concordance of genomic alterations between tissue and plasma circulating tumor DNA in metastatic melanoma

AU - Calapre, Leslie

AU - Giardina, Tindaro

AU - Robinson, Cleo

AU - Reid, Anna L

AU - Al-Ogaili, Zeyad

AU - Pereira, Michelle R

AU - McEvoy, Ashleigh C

AU - Warburton, Lydia

AU - Hayward, Nicholas K

AU - Khattak, Muhammad A

AU - Meniawy, Tarek M

AU - Millward, Michael

AU - Amanuel, Benhur

AU - Ziman, Melanie

AU - Gray, Elin S

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AB - Circulating tumor DNA (ctDNA) may serve as a surrogate to tissue biopsy for noninvasive identification of mutations across multiple genetic loci and for disease monitoring in melanoma. In this study, we compared the mutation profiles of tumor biopsies and plasma ctDNA from metastatic melanoma patients using custom sequencing panels targeting 30 melanoma-associated genes. Somatic mutations were identified in 20 of 24 melanoma biopsies, and 16 of 20 (70%) matched-patient plasmas had detectable ctDNA. In a subgroup of seven patients for whom matching tumor tissue and plasma were sequenced, 80% of the mutations found in tumor tissue were also detected in ctDNA. However, TERT promoter mutations were only detected by ddPCR, and promoter mutations were consistently found at lower concentrations than other driver mutations in longitudinal samples. In vitro experiments revealed that mutations in promoter regions of TERT and DPH3 are underrepresented in ctDNA. While the results underscore the utility of using ctDNA as an alternative to tissue biopsy for genetic profiling and surveillance of the disease, our study highlights the underrepresentation of promoter mutations in ctDNA and its potential impact on quantitative liquid biopsy applications.

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JO - Molecular Oncology

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