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Original Investigation
July 2016

Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal TumorsA Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic

Author Affiliations
  • 1Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
  • 2now with Sarcoma and Rare Tumors Program, Division of Hematology, Oncology, and Palliative Care, Massey Cancer Center, Virginia Commonwealth University, Richmond
  • 3Department of Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 4Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
  • 5Pediatric Surgical Service, Memorial Sloan Kettering Cancer Center, New York, New York
  • 6Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts
  • 7Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 8Division of Hematology/Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
  • 9Division of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
  • 10Pediatric Hematology and Oncology, Huntsman Cancer Institute, Salt Lake City, Utah
  • 11Division of Intramural Research, National Institute of Child Health and Human Development, Bethesda, Maryland
  • 12Section of Medical Neuroendocrinology, National Institute of Child Health and Human Development, Bethesda, Maryland
  • 13Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
  • 14Section of Endocrinology and Genetics, National Institute of Child Health and Human Development, Bethesda, Maryland
  • 15Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, Massachusetts
JAMA Oncol. 2016;2(7):922-928. doi:10.1001/jamaoncol.2016.0256

Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.