title: Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic.
abstract: OBJECTIVE
  Wild-type (WT) gastrointestinal stromal tumors (GISTs), which lack KIT and PDGFRA gene mutations, are the primary form of GIST in children and occasionally occur in adults. They respond poorly to standard targeted therapy. Better molecular and clinical characterization could improve management.
  
  
  OBJECTIVE
  To evaluate the clinical and tumor genomic features of WT GIST.
  
  
  METHODS
  Patients enrolled in an observational study at the National Institutes of Health starting in 2008 and were evaluated in a GIST clinic held once or twice yearly. Patients provided access to existing medical records and tumor specimens. Self-referred or physician-referred patients younger than 19 years with GIST or 19 years or older with known WT GIST (no mutations in KIT or PDGFRA) were recruited; 116 patients with WT GIST were enrolled, and 95 had adequate tumor specimen available. Tumors were characterized by immunohistochemical analysis (IHC) for succinate dehydrogenase (SDH) subunit B, sequencing of SDH genes, and determination of SDHC promoter methylation. Testing of germline SDH genes was offered to consenting patients and families.
  
  
  METHODS
  For classification, tumors were characterized by SDHA, B, C, or D (SDHX) mutations and other genetic and epigenetic alterations, including presence of mutations in germline. Clinical characteristics were categorized.
  
  
  RESULTS
  Wild-type GIST specimens from 95 patients (median age, 23 [range, 7-78] years; 70% female) were classified into 3 molecular subtypes: SDH-competent (n = 11), defined by detection of SDHB by IHC; and 2 types of SDH-deficient GIST (n = 84). Of SDH-deficient tumors, 63 (67%) had SDH mutations, and in 31 of 38 (82%), the SDHX mutation was also present in germline. Twenty-one (22%) SDH-deficient tumors had methylation of the SDHC promoter leading to silencing of expression. Mutations in known cancer-associated pathways were identified in 9 of 11 SDH-competent tumors. Among patients with SDH-mutant tumors, 62% were female (39 of 63), median (range) age was 23 (7-58) years, and approximately 30% presented with metastases (liver [12 of 58], peritoneal [6 of 58], lymph node [15 of 23]). SDHC-epimutant tumors mostly affected young females (20 of 21; median [range] age, 15 [8-50] years), and approximately 40% presented with metastases (liver [7 of 19], peritoneal [1 of 19], lymph node [3 of 8]). SDH-deficient tumors occurred only in the stomach and had an indolent course.
  
  
  CONCLUSIONS
  An observational study of WT GIST permitted the evaluation of a large number of patients with this rare disease. Three molecular subtypes with implications for prognosis and clinical management were identified.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland2now with Sarcoma and Rare Tumors Program, Division of Hematology, Oncology, and Palliative Care, Massey Cancer Center, Virginia Commonwealth University, R.
authors.forename: Sosipatros A
authors.initials: SA
authors.lastname: Boikos
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Alberto S
authors.initials: AS
authors.lastname: Pappo
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: J Keith
authors.initials: JK
authors.lastname: Killian
authors.affiliation: Pediatric Surgical Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael P
authors.initials: MP
authors.lastname: LaQuaglia
authors.affiliation: Department of Surgery, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Chris B
authors.initials: CB
authors.lastname: Weldon
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Suzanne
authors.initials: S
authors.lastname: George
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Trent
authors.affiliation: Division of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.affiliation: Pediatric Hematology and Oncology, Huntsman Cancer Institute, Salt Lake City, Utah.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wright
authors.affiliation: Pediatric Hematology and Oncology, Huntsman Cancer Institute, Salt Lake City, Utah.
authors.forename: Josh D
authors.initials: JD
authors.lastname: Schiffman
authors.affiliation: Division of Intramural Research, National Institute of Child Health and Human Development, Bethesda, Maryland.
authors.forename: Margarita
authors.initials: M
authors.lastname: Raygada
authors.affiliation: Section of Medical Neuroendocrinology, National Institute of Child Health and Human Development, Bethesda, Maryland.
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Markku M
authors.initials: MM
authors.lastname: Miettinen
authors.affiliation: Section of Endocrinology and Genetics, National Institute of Child Health and Human Development, Bethesda, Maryland.
authors.forename: Constantine
authors.initials: C
authors.lastname: Stratakis
authors.affiliation: Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Janeway
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Helman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D019175:DNA Methylation / Q000235:genetics; D042963:Electron Transport Complex II / Q000235:genetics*; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000145:classification / Q000235:genetics* / Q000473:pathology; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C108096:SDHC protein, human; C491545:SDHD protein, human; D042963:Electron Transport Complex II; C511268:SDHA protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha