Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors.
Adult
Aged
Biomarkers, Tumor
Cell-Free Nucleic Acids
Circulating Tumor DNA
Exons
Female
Gastrointestinal Stromal Tumors
/ blood
Genotype
High-Throughput Nucleotide Sequencing
Humans
Liquid Biopsy
Male
Middle Aged
Molecular Targeted Therapy
Mutation
Neoplasm Metastasis
Polymerase Chain Reaction
Prognosis
Protein Kinase Inhibitors
/ pharmacology
Tumor Burden
Circulating tumor DNA
Gastrointestinal stromal tumor
Imatinib
KIT
Liquid biopsy
PDGFRA
Regorafenib
Sarcoma
Sunitinib
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
05 Feb 2020
05 Feb 2020
Historique:
received:
16
07
2019
accepted:
31
01
2020
entrez:
7
2
2020
pubmed:
7
2
2020
medline:
27
10
2020
Statut:
epublish
Résumé
Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients. We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR). We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib. ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.
Sections du résumé
BACKGROUND
BACKGROUND
Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients.
METHODS
METHODS
We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR).
RESULTS
RESULTS
We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib.
CONCLUSIONS
CONCLUSIONS
ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.
Identifiants
pubmed: 32024476
doi: 10.1186/s12885-020-6597-x
pii: 10.1186/s12885-020-6597-x
pmc: PMC7003348
doi:
Substances chimiques
Biomarkers, Tumor
0
Cell-Free Nucleic Acids
0
Circulating Tumor DNA
0
Protein Kinase Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
99Subventions
Organisme : FERO Foundation
ID : 2015
Organisme : Fundación Científica Asociación Española Contra el Cáncer
ID : JP Barcelona
Organisme : Instituto de Salud Carlos III
ID : PI16/01371
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