Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors
Serrano, Cesar (Vall d'Hebron Institut d'Oncologia)
Vivancos, Ana (Vall d'Hebron Institut d'Oncologia)
López Pousa, Antonio (Institut d'Investigació Biomèdica Sant Pau)
Matito, Judit (Vall d'Hebron Institut d'Oncologia)
Mancuso, Francesco M. (Vall d'Hebron Institut d'Oncologia)
Valverde, Claudia (Hospital Universitari Vall d'Hebron)
Quiroga, Sergi (Hospital Universitari Vall d'Hebron)
Landolfi, Stefania (Hospital Universitari Vall d'Hebron)
Castro, Sandra (Hospital Universitari Vall d'Hebron)
Dopazo, Cristina (Hospital Universitari Vall d'Hebron)
Sebio, Ana (Institut d'Investigació Biomèdica Sant Pau)
Virgili Manrique, Anna Cristina (Institut d'Investigació Biomèdica Sant Pau)
Menso, Maria M. (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Martín-Broto, J. (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Sansó, Miriam (Vall d'Hebron Institut d'Oncologia)
García-Valverde, Alfonso (Vall d'Hebron Institut d'Oncologia)
Rosell Aluja, Jordi 1955- (Vall d'Hebron Institut d'Oncologia)
Fletcher, J.A. (Harvard Medical School)
George, S. (Dana-Farber Cancer Institute (Boston, Estats Units d'Amèrica))
Carles, Joan (Hospital Universitari Vall d'Hebron)
Arribas, Joaquín V (Vall d'Hebron Institut d'Oncologia)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Circulating tumor DNA ; Gastrointestinal stromal tumor ; Imatinib ; KIT ; Liquid biopsy ; PDGFRA ; Regorafenib ; Sarcoma ; Sunitinib
Published in:	BMC Cancer, Vol. 20 Núm. 1 (may 2020) , p. 99, ISSN 1471-2407

DOI: 10.1186/s12885-020-6597-x
PMID: 32024476

12 p, 1.3 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles