Značaj mutacija u genima KIT i PDGFRA u evaluaciji lečenja bolesnika operisanih zbog gastrointestinalnog stromalnog tumora želuca

Abstract

Cilj: Ispitivanje genetskih mutacija na KIT i PDGFRA genima, prikazivanje njihove učestalosti, vrste mutacija i korelacije ovih specifičnih genskih mutacija sa patohistološkim i imunohistohemijskim karakteristikama tumora. Korelacija genetskih mutacija na KIT i PDGFRA sa kliničkim tokom operisanih bolesnika. Metod: Prospektivna i delimično retrospektivna klinička studija koja je uključila 100 bolesnika operisane zbog GIST-a želuca u period od 2005 do 2016 godine. Načinjena je molekularna analiza na parafinskim kalupima tumorskog tkiva, a kod 45 bolesnika kod kojih su identifikovane KIT i PDGFRA mutacije sprovedena je dalja analiza, sa posebnim osvrtom na patološke karakteristike tumora, recidiv oboljenja i ukupno preživljavanje, te procena uticaja analiziranih genskih mutacija na navedene promene. Rezultati: Od 100 operisanih bolesnika 46% su u grupi visokog rizika od kojih kod 54% nastaju metastaze ili lokalni recidiv. Od ukupno 100 ispitivanih bolesnika, kod 45 bolesnika je dobijen mutacioni status, gde su 37 (82%) bolesnika sa KIT mutacijama, 6 (14%) bolesnika sa PDGFRA mutacije i 2 (4%) bolesnika svrstani u "wild type". Analizom krive preživljavanja kod bolesnika operisanih zbog GIST želuca utvrđena je značajna razlika u javljanju metastaze i smrtnog ishoda u zavisnosti od tipa mutacije(p=0.023). Cox-ovim regresionom analizom je pokazano da bolesnici visokog rizika sa recidivom bolesti koji nisu primali Imatinib imali su 7 puta veću verovatnoću smrtnog ishoda u odnosu na bolesnike lečene Imatinobom Zaključak: Analiza mutacije na KIT i PDGFRA genima ima prognostički i prediktivni značaj kod bolesnika operisanih zbog GIST želuca. Imatinib ima značajnu ulogu u lečenju bolesnika koji su u grupi viskog rizika.

Objective: KIT (KIT proto-oncogene receptor tyrosine kinase) and PDGFRA (Platelet derived growth factor receptor alpha) gene mutations represent major molecular forces inside the gastrointestinal stromal tumors (GIST). Aim of this study was to evaluate these mutations in patients who underwent surgical resection of gastric GIST Methods: Retrospective clinical study included 100 patients who were operated due to gastric GIST from 2005 till 2016. Molecular analysis of paraffin embedded tumor tissue was performed, and the 45 patients who had presence of KIT and PDGFRA mutations were further evaluated, with regard to pathological tumor stage, disease recurrence and overall survival. Results: Of the 100 patients who were operated 46% are in the high risk group of which at 54% of the resulting metastasis or local recurrence. From a total of 100 patients, in 45 patients we obtained mutational status, where 37 (82%) of patients had KIT mutations, 6 (14%) patients had PDGFRA mutations and 2 (4%) patients were classified into the “ wild-type”. The analysis of survival curves in patients surgically treated for gastric GIST showed a significant difference in emergence of metastases and death depending on the type of mutation (p = 0.023). Cox's regression analysis shown that patients with a high risk of recurrent disease who were not receiving Imatinib had the 7 times greater probability of fatal outcome compared to patients treated with Imatinib. Conclusion: Analysis of mutations in the genes KIT and PDGFRA has prognostic and predictive significance in patients surgically treated for gastric GIST. Imatinib has an important role in the treatment of patients who are in the group of high risk.