biostudies-literatureUnknown12Ko TKAgency for Science, Technology and ResearchSingHealth FoundationDuke-NUS Medical SchoolNational Medical Research CouncilLiquid biopsy circulating tumor DNA (ctDNA)-based approaches may represent a non-invasive means for molecular interrogation of gastrointestinal stromal tumors (GISTs). We deployed a customized 29-gene Archer^® LiquidPlex™ targeted panel on 64 plasma samples from 46 patients. The majority were known to harbor <i>KIT</i> mutations (<i>n</i> = 41, 89.1%), while 3 were <i>PDGFRA</i> exon 18 D842V mutants and the rest (<i>n</i> = 2) were wild type for <i>KIT</i> and <i>PDGFRA</i>. In terms of disease stage, 14 (30.4%) were localized GISTs that had undergone complete surgical resection while the rest (<i>n</i> = 32) were metastatic. Among ten patients, including 7 on tyrosine kinase inhibitors, with evidence of disease progression at study inclusion, mutations in ctDNA were detected in 7 cases (70%). Known somatic mutations in <i>KIT</i> (<i>n</i> = 5) or <i>PDGFRA</i> (<i>n</i> = 1) in ctDNA were identified only among 6 of the 10 patients. These <i>KIT</i> mutants included duplication, indels, and single-nucleotide variants. The median mutant AF in ctDNA was 11.0% (range, 0.38%-45.0%). In patients with metastatic progressive <i>KIT</i>-mutant GIST, tumor burden was higher with detectable <i>KIT</i> ctDNA mutation than in those without (median, 5.97 cm vs. 2.40 cm, <i>p</i> = 0.0195). None of the known tumor mutations were detected in ctDNA for localized cases (<i>n</i> = 14) or metastatic cases without evidence of disease progression (<i>n</i> = 22). In patients with serial samples along progression of disease, secondary acquired mutations, including a potentially actionable <i>PIK3CA</i> exon 9 c.1633G>A mutation, were detected. ctDNA mutations were not detectable when patients responded to a switch in TKI therapy. In conclusion, detection of GIST-related mutations in ctDNA using a customized targeted NGS panel represents an attractive non-invasive means to obtain clinically tractable information at the time of disease progression.Frontiers in oncology840843https://www.ebi.ac.uk/biostudies/studies/S-EPMC8904145biostudies-literatureCirculating Tumor DNA Mutations in Progressive Gastrointestinal Stromal Tumors Identify Biomarkers of Treatment Resistance and Uncover Potential Therapeutic Strategies.PMC8904145Ko TKSomasundaram NYang VSNg CCTeh BTFarid MLee EChan JYfalseCirculating Tumor DNA Mutations in Progressive Gastrointestinal Stromal Tumors Identify Biomarkers of Treatment Resistance and Uncover Potential Therapeutic Strategies.Liquid biopsy circulating tumor DNA (ctDNA)-based approaches may represent a non-invasive means for molecular interrogation of gastrointestinal stromal tumors (GISTs). We deployed a customized 29-gene Archer^® LiquidPlex™ targeted panel on 64 plasma samples from 46 patients. The majority were known to harbor <i>KIT</i> mutations (<i>n</i> = 41, 89.1%), while 3 were <i>PDGFRA</i> exon 18 D842V mutants and the rest (<i>n</i> = 2) were wild type for <i>KIT</i> and <i>PDGFRA</i>. In terms of disease stage, 14 (30.4%) were localized GISTs that had undergone complete surgical resection while the rest (<i>n</i> = 32) were metastatic. Among ten patients, including 7 on tyrosine kinase inhibitors, with evidence of disease progression at study inclusion, mutations in ctDNA were detected in 7 cases (70%). Known somatic mutations in <i>KIT</i> (<i>n</i> = 5) or <i>PDGFRA</i> (<i>n</i> = 1) in ctDNA were identified only among 6 of the 10 patients. These <i>KIT</i> mutants included duplication, indels, and single-nucleotide variants. The median mutant AF in ctDNA was 11.0% (range, 0.38%-45.0%). In patients with metastatic progressive <i>KIT</i>-mutant GIST, tumor burden was higher with detectable <i>KIT</i> ctDNA mutation than in those without (median, 5.97 cm vs. 2.40 cm, <i>p</i> = 0.0195). None of the known tumor mutations were detected in ctDNA for localized cases (<i>n</i> = 14) or metastatic cases without evidence of disease progression (<i>n</i> = 22). In patients with serial samples along progression of disease, secondary acquired mutations, including a potentially actionable <i>PIK3CA</i> exon 9 c.1633G>A mutation, were detected. ctDNA mutations were not detectable when patients responded to a switch in TKI therapy. In conclusion, detection of GIST-related mutations in ctDNA using a customized targeted NGS panel represents an attractive non-invasive means to obtain clinically tractable information at the time of disease progression.2022-01-01T00:00:00Z20222025-04-04T14:49:53.604Z2025-04-04T14:49:53.604ZS-EPMC89041453527391710.3389/fonc.2022.840843