PURPOSE: Mutated KIT and platelet-derived growth factor alpha gene (PDGFRA) drive GI stromal tumor (GIST) oncogenesis, but the clinical significance of their single mutations is known incompletely. PATIENTS AND METHODS: We identified 11 population-based series of patients with GIST through a literature search and pooled individual data from 3,067 patients treated with macroscopically complete tumor excision. Mutation analysis was done from 1,505 tumors. We analyzed associations between KIT and PDGFRA mutations and recurrence-free survival (RFS) in the subsets in which patients were treated with surgery alone. RESULTS: We identified 301 different single mutations in KIT and 33 in PDGFRA. Patients with PDGFRA mutations had more favorable RFS than those with KIT mutations (hazard ratio, 0.34; P = .004). Only one of the 35 GISTs with KIT exon 11 duplication mutations recurred. Patients with deletions of only one codon of KIT exon 11 had better RFS than those with another deletion type, and some KIT exon 11 substitution mutations (Trp557Arg, Val559Ala, and Leu576Pro) were also associated with favorable RFS. Patients with an identical mutation had greatly variable outcomes depending on the standard prognostic factors, notably, mitotic count. Commonly used risk stratification schemes tended to overestimate the risk for recurrence in subgroups with prognostically favorable mutations. CONCLUSION: GISTs with an identical KIT or PDGFRA mutation may have widely varying risks for recurrence. Most of the patients with PDGFRA mutations and those with KIT exon 11 duplication mutation or deletion of one codon have favorable RFS with surgery alone and are usually not candidates for adjuvant therapy.

Heikki Joensuu Helsinki University Central Hospital Helsinki Finland; Piotr Rutkowski Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology Warsaw Poland; Toshirou Nishida National Cancer Center Hospital East Kashiwa Japan; Sonja E Steigen University Hospital of North Norway and Tumor Biology Research Group UiT The Arctic University of Norway Tromsø Norway; Peter Brabec Institute of Biostatistics and Analyses Masaryk University Brno Czech Republic; Lukas Plank Jessenius Medical Faculty of Comenius University and University Hospital Martin; Jozef Sufliarsky National Cancer Institute Bratislava Slovak Republic; Bengt Nilsson Sahlgrenska University Hospital Gothenburg Sweden; Chiara Braconi Centro Regionale di Genetica Oncologica Oncologia Medica Ancona; Massimo Federico University of Modena and Reggio Emilia Modena Italy; Chiara Braconi The Institute of Cancer Research Belmont United Kingdom; Andrea Bordoni Ticino Cancer Registry Insitute of Pathology South of Switzerland Locarno Switzerland; Magnus K Magnusson University of Iceland; Jon G Jonasson Landspitali The National University Hospital of Iceland Reykjavik Iceland; Isabelle Hostein Bergonié Institute Bordeaux; Pierre Paul Bringier E Herriot Hospital Lyon; Jean Francois Emile Versailles University and Assistance Publique Hôpitaux de Paris Ambroise Paré Hospital Boulogne France

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