title: Intratumoral KIT mutational heterogeneity and recurrent KIT/ PDGFRA mutations in KIT/PDGFRA wild-type gastrointestinal stromal tumors.
abstract: OBJECTIVE
  Gastrointestinal stromal tumors (GISTs) with no mutations in exons 9, 11, 13, and 17 of the KIT gene and exons 12, and 18 of the PDGFRA gene were defined as KIT/PDGFRA wild-type and they accounted for ~15-20% of GISTs. However, some KIT/PDGFRA wild-type GISTs with KIT mutations in other exons were occasionally reported. We therefore assessed GISTs to understand the whole genomic genotypes of KIT or PDGFRA genes in KIT/PDGFRA wild-type GISTs.
  
  
  METHODS
  A cohort of 185 KIT/PDGFRA wild-type GISTs from 1,080 cases was retrospectively assessed. Thirty-nine patients were excluded due to insufficiency of genomic DNA data or failure of library preparation, and 146 patients were analyzed by targeted next-generation sequencing (NGS) followed by validation.
  
  
  RESULTS
  For hot spots in KIT and PDGFRA genes, 23 out of 146 KIT/PDGFRA wild-type cases carried mutations according to NGS; there were 19 KIT mutations and 4 PDGFRA mutations, and these were exclusive. Intratumoral KIT mutational heterogeneity was observed in 4 of 19 samples which potentially triggered mechanisms of polyclonal evolution and metastasis and drug sensitivity. Eleven patients treated with imatinib were evaluable for clinical response, and 2 of 3 patients with KIT mutations achieved partial response (PR), while only 1 of 8 patients without KIT mutations reached PR.
  
  
  CONCLUSIONS
  NGS had the potential property to identify partial mutant tumors from a subset of GISTs regarded as KIT/PDGFRA wild-type tumors using Sanger sequencing, and provided a better understanding of KIT/PDGFRA genotypes as well as identified patients eligible for imatinib therapy.
authors: Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Jing
authors: J
authors: Gao
authors: Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Jian
authors: J
authors: Li
authors: Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Yanyan
authors: Y
authors: Li
authors: Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Zhongwu
authors: Z
authors: Li
authors: Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Jifang
authors: J
authors: Gong
authors: MyGenostics Inc. Beijing, China.
authors: Jian
authors: J
authors: Wu
authors: MyGenostics Inc. Beijing, China.
authors: Na
authors: N
authors: Liu
authors: Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Bin
authors: B
authors: Dong
authors: Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Changsong
authors: C
authors: Qi
authors: Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Jie
authors: J
authors: Li
authors: Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Lin
authors: L
authors: Shen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: KIT/PDGFRA mutation; imatinib; intratumoral heterogeneity; next-generation sequencing; wild-type GISTs