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KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence
Heikki Joensuu1, Piotr Rutkowski2, Toshirou Nishida2
1Heikki 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. heikki.joensuu@hus.fi.
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.
Insights
KIT and PDGFRA mutations impact gastrointestinal stromal tumor (GIST) recurrence. PDGFRA mutations and specific KIT mutations, like exon 11 duplications, predict favorable recurrence-free survival after surgery alone.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Mutations in KIT and platelet-derived growth factor alpha gene (PDGFRA) are key drivers of gastrointestinal stromal tumor (GIST) oncogenesis.
- The precise clinical significance of individual KIT and PDGFRA mutations in GIST prognosis remains incompletely understood.
Purpose of the Study:
- To investigate the clinical significance of specific KIT and PDGFRA mutations in relation to recurrence-free survival (RFS) in patients with GIST.
- To evaluate the impact of different mutation types on GIST recurrence risk following surgical resection.
Main Methods:
- A literature search identified 11 population-based GIST series, pooling data from 3,067 patients.
- Mutation analysis was performed on 1,505 GIST tumors.
- Associations between KIT/PDGFRA mutations and RFS were analyzed in patients treated with surgery alone.
Main Results:
- 301 KIT and 33 PDGFRA single mutations were identified.
- PDGFRA mutations were associated with significantly more favorable RFS compared to KIT mutations (HR 0.34, P = .004).
- Specific KIT mutations, including exon 11 duplications, single-codon deletions, and certain substitutions (Trp557Arg, Val559Ala, Leu576Pro), correlated with favorable RFS. Risk stratification schemes often overestimated recurrence risk in these subgroups.
Conclusions:
- GISTs with identical KIT or PDGFRA mutations exhibit variable recurrence risks.
- Patients with PDGFRA mutations, KIT exon 11 duplication, or single-codon deletion mutations generally have favorable RFS with surgery alone.
- These findings suggest that many patients with specific favorable mutations may not require adjuvant therapy.
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