KIT exon 10 variant (c.1621 A > C) single nucleotide polymorphism as predictor of GIST patient outcome.
BACKGROUND
Tumor genotype plays a crucial role in clinical management of GIST. Whether genetic polymorphism of KIT may influence GIST patient outcome is unclear.


METHODS
We investigated the biological and clinical significance of the presence of KIT exon 10 variant (c.1621 A > C), KIT (L541), in a transfected cell line (3 T3 L541) and in two retrospectively collected series of 109 GIST patients in total. The control group consisted of 60 healthy donors collected at the French department of blood transfusion.


RESULTS
In the 3 T3 L541 cell line, KIT(L541) protein exhibited a spontaneous phosphorylation status comparable to that of wild-type KIT but displayed a phosphorylation pattern of AKT and ERK1/2 that was found similar to that of the classical mutated forms of the KIT receptor. Of 109 patients enrolled in this retrospective translational research study, 24 (22%) harboured KIT (L541), similarly to the control group of healthy donors (n = 10 of 60, 17%). A higher prevalence of the variant KIT (L541) was observed in patients with metastatic status at diagnosis (KIT (L541) correlated nine of 22 versus 15 of 87, p = 0.02). In addition, patients with KIT (L541) and localized GIST had a higher rate of relapse at 5 years and lower relapse free survival at 5 years in univariate, as well as in multivariate analysis. Response rate and duration of response to imatinib was similar in KIT (L541) and KIT (M541) patients.


CONCLUSIONS
KIT (L541) genotype is associated with a higher risk of metastasis at diagnosis and a higher risk of relapse in GIST patients.
Department of medical oncology, Centre Leon Berard, 28 rue Laennec, Lyon, France. mehdi.brahmi@hotmail.fr.
Mehdi
M
Brahmi
Cancer Research Center of Lyon, INSERM UMR 1052, CNRS UMR 5286, Centre Leon Berard, 28 rue Laennec, Lyon, France. laurent.alberti@lyon.unicancer.fr.
Laurent
L
Alberti
Cancer Research Center of Lyon, INSERM UMR 1052, CNRS UMR 5286, Centre Leon Berard, 28 rue Laennec, Lyon, France. a.dufresne@hotmail.fr.
Armelle
A
Dufresne
Department of medical oncology, Centre Leon Berard, 28 rue Laennec, Lyon, France. isabelle.ray-coquard@lyon.unicancer.fr.
Isabelle
I
Ray-Coquard
Department of medical oncology, Centre Leon Berard, 28 rue Laennec, Lyon, France. philippe.cassier@lyon.unicancer.fr.
Philippe
P
Cassier
Department of medical oncology, Centre Leon Berard, 28 rue Laennec, Lyon, France. pierre.meeus@lyon.unicancer.fr.
Pierre
P
Meeus
Pathology Department, Centre Leon Berard, 28 rue Laennec, Lyon, France. anne-valerie.decouvelaere@lyon.unicancer.fr.
Anne-Valérie
AV
Decouvelaere
Pathology Department, Centre Leon Berard, 28 rue Laennec, Lyon, France. dominique.ranchere-vince@lyon.unicancer.fr.
Dominique
D
Ranchère-Vince
Department of medical oncology, Centre Leon Berard, 28 rue Laennec, Lyon, France. jean-yves.blay@lyon.unicancer.fr.
Jean-Yves
JY
Blay
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D012008:Recurrence; D012189:Retrospective Studies; D055815:Young Adult
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt