Pitfalls in mutational testing and reporting of common KIT and PDGFRA mutations in gastrointestinal stromal tumors.
BACKGROUND
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. 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.


METHODS
When 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.


RESULTS
We 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.


CONCLUSIONS
By 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.
Merkelbach-Bruse
Sabine
S
Department of Pathology, University of Bonn Medical School, Sigmund-Freud-Str, 25 D-53127 Bonn, Germany. sabine.merkelbach-bruse@ukb.uni-bonn.de
Dietmaier
Wolfgang
W
Füzesi
Laszlo
L
Gaumann
Andreas
A
Haller
Florian
F
Kitz
Julia
J
Krohn
Antje
A
Mechtersheimer
Gunhild
G
Penzel
Roland
R
Schildhaus
Hans-Ulrich
HU
Schneider-Stock
Regine
R
Simon
Ronald
R
Wardelmann
Eva
E
D001549:Benzamides; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005091:Exons; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D005858:Germany; D006801:Humans; D000068877:Imatinib Mesylate; D009154:Mutation; D010879:Piperazines; D011379:Prognosis; D011743:Pyrimidines; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha