title: Gain of TP53 Mutation in Imatinib-treated SDH-Deficient Gastrointestinal Stromal Tumor and Clinical Utilization of Targeted Next-generation Sequencing Panel for Therapeutic Decision Support.
abstract: Patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) have few therapeutic options. Despite lack of KIT or platelet-derived growth factor receptor A (PDGFRA) driver mutations, SDH-deficient GISTs display strong expression of KIT by immunohistochemistry and these patients are often treated with tyrosine kinase inhibitors, including imatinib as a first-line therapy. Using a targeted next-generation sequencing panel of mutation hotspots of 50-clinically relevant genes, we investigated (1) concurrence of somatic/actionable mutations and (2) tumor molecular evolution by comparing 2 resection specimens 1.5 years apart while the patient was on imatinib adjuvant therapy. We found the tumors did not harbor KIT, PDGFRA, or any other clinically actionable mutations. However, a TP53 mutation (c.422G>A; p.C141Y) was detected in the second recurrent lesion. This represents the first study to monitor the molecular evolution of a SDH-deficient GIST during adjuvant treatment. These findings emphasize the critical need for next-generation sequencing testing before initiating targeted therapy.
authors.affiliation: Department of Pathology, University of Southern California, Keck School of Medicine.
authors.forename: Christina H
authors.initials: CH
authors.lastname: Wei
authors.affiliation: Keck Medicine of USC, Los Angeles, CA.
authors.forename: Jonas
authors.initials: J
authors.lastname: Pettersson
authors.affiliation: Keck Medicine of USC, Los Angeles, CA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Campan
authors.affiliation: Department of Pathology, University of Southern California, Keck School of Medicine.
authors.forename: Shefali
authors.initials: S
authors.lastname: Chopra
authors.affiliation: Department of Pathology, University of Southern California, Keck School of Medicine.
authors.forename: Wesley
authors.initials: W
authors.lastname: Naritoku
authors.affiliation: Department of Pathology, University of Southern California, Keck School of Medicine.
authors.forename: Sue E
authors.initials: SE
authors.lastname: Martin
authors.affiliation: Department of Pathology, University of Southern California, Keck School of Medicine.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Ward
mesh_terms: D000328:Adult; D000066491:Clinical Decision-Making; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage*; D020125:Mutation, Missense; D013385:Succinate Dehydrogenase / Q000172:deficiency*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000068877:Imatinib Mesylate; D013385:Succinate Dehydrogenase