{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Denu RA"],"funding":["MD Anderson Cancer Center Support Grant","NIH grant","NCI NIH HHS"],"pagination":["1707"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11083047"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["16(9)"],"pubmed_abstract":["<b>Objective:</b> The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in <i>KIT</i>, <i>PDGFRA</i>, or components of the succinate dehydrogenase (SDH) complex (<i>SDHA</i>, <i>SDHB</i>, <i>SDHC</i>, and <i>SDHD</i> genes). A small fraction of GISTs lack alterations in <i>KIT</i>, <i>PDGFRA</i>, and <i>SDH</i>. We aimed to further characterize the clinical and genomic characteristics of these so-called \"triple-negative\" GISTs. <b>Methods:</b> We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify \"triple-negative\" patients. <b>Results:</b> Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5-191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a <i>BRAF</i> V600E mutation and two with <i>NF1</i> loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with <i>TP53</i> LOF mutations, one with <i>NTRK3</i> fusion (<i>ETV6-NTRK3</i>), one with <i>PTEN</i> deletion, one with <i>FGFR1</i> gain-of-function (GOF) mutation (K654E), one with <i>CHEK2</i> LOF mutation (T367fs*), one with Aurora kinase A fusion (<i>AURKA-CSTF1</i>), and one with <i>FANCA</i> deletion. Patients had better responses with molecularly targeted therapies than with imatinib. <b>Conclusions:</b> Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to <i>KIT</i>/<i>PDGFRA</i>-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy."],"journal":["Cancers"],"pubmed_title":["Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors."],"pmcid":["PMC11083047"],"funding_grant_id":["P30 CA016672","T32 CA009666"],"pubmed_authors":["Denu RA","Ravi V","Lazar AJ","Urquiola ES","Nakazawa MS","Araujo DM","Byrd PS","Ratan R","Nassif Haddad EF","Wang WL","Joseph CP","Yang RK","Patel S","Zarzour MA","Conley AP","Somaiah N"],"additional_accession":[]},"is_claimable":false,"name":"Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors.","description":"<b>Objective:</b> The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in <i>KIT</i>, <i>PDGFRA</i>, or components of the succinate dehydrogenase (SDH) complex (<i>SDHA</i>, <i>SDHB</i>, <i>SDHC</i>, and <i>SDHD</i> genes). A small fraction of GISTs lack alterations in <i>KIT</i>, <i>PDGFRA</i>, and <i>SDH</i>. We aimed to further characterize the clinical and genomic characteristics of these so-called \"triple-negative\" GISTs. <b>Methods:</b> We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify \"triple-negative\" patients. <b>Results:</b> Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5-191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a <i>BRAF</i> V600E mutation and two with <i>NF1</i> loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with <i>TP53</i> LOF mutations, one with <i>NTRK3</i> fusion (<i>ETV6-NTRK3</i>), one with <i>PTEN</i> deletion, one with <i>FGFR1</i> gain-of-function (GOF) mutation (K654E), one with <i>CHEK2</i> LOF mutation (T367fs*), one with Aurora kinase A fusion (<i>AURKA-CSTF1</i>), and one with <i>FANCA</i> deletion. Patients had better responses with molecularly targeted therapies than with imatinib. <b>Conclusions:</b> Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to <i>KIT</i>/<i>PDGFRA</i>-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Apr","modification":"2026-04-08T18:31:28.076Z","creation":"2026-04-08T09:38:48.402Z"},"accession":"S-EPMC11083047","cross_references":{"pubmed":["38730662"],"doi":["10.3390/cancers16091707"]}}