Abstract
BackgroundMutation analysis of KIT and PDGFRA genes in gastrointestinal stromal tumors is gaining increasing importance for prognosis of GISTs and for prediction of treatment response. Several groups have identified specific mutational subtypes in KIT exon 11 associated with an increased risk of metastatic disease whereas GISTs with PDGFRA mutations often behave less aggressive. Furthermore, in advanced GIST disease with proven KIT exon 9 mutation the doubled daily dose of 800 mg imatinib increases the progression free survival and is now recommended both in the European and the American Guidelines. In Germany, there are still no general rules how to perform mutational analysis.MethodsWhen comparing results from six different molecular laboratories we recognized the need of standardisation. Six German university laboratories with experience in mutation analysis in GISTs joined together to develop recommendations for the mutation analysis of the most common and clinically relevant hot spots, i. e. KIT exons 9 and 11 and PDGFRA exon 18. We performed a three-phased interlaboratory trial to identify pitfalls in performing molecular analysis in GISTs.ResultsWe developed a design for a continuous external laboratory trial. In 2009 this external trial was conducted by 19 laboratories via the initiative for quality assurance in pathology (QuiP) of the German Society of Pathology and the Professional Association of German Pathologists.ConclusionsBy performing a three-phased internal interlaboratory trial and conducting an external trial in Germany we were able to identify potential pitfalls when performing KIT and PDGFRA mutational analysis in gastrointestinal stromal tumors. We developed standard operation procedures which are provided with the manuscript to allow other laboratories to prevent these pitfalls.
Highlights
Mutation analysis of KIT and PDGFRA genes in gastrointestinal stromal tumors is gaining increasing importance for prognosis of Gastrointestinal stromal tumors (GISTs) and for prediction of treatment response
As a strongly simplified rule one can suppose that about 65% of all GISTs harbour primary KIT exon 11 mutations, whereas KIT exon 9 and PDGFRA exon 18 mutations account each for about 10% of primary mutations
Concerning the samples T1.3, T1.6 and T1.10, there was accordance in five labs, one lab each failed to detect the mutation in KIT exon 11 or PDGFRA exon 18 due to high background peaks (Fig. 1a)
Summary
Mutation analysis of KIT and PDGFRA genes in gastrointestinal stromal tumors is gaining increasing importance for prognosis of GISTs and for prediction of treatment response. The remaining 5% may carry mutations in the exons 13 or 17 of KIT or in exons 12 or 14 of PDGFRA, so the frequency in each of these regions is below 1% [5,6]. For these latter regions there is no experience concerning their prognostic and predictive value, we decided to restrict our study to the most important and clinically relevant exons, i.
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