Significance of KIT and PDGFRA mutations in gastric gastrointestinal stromal tumor imatinib-naive surgically treated patients

Keramatollah A Ebrahimi; Predrag Sabljak; Aleksandar P Simić; Ognjan M Skrobić; Dejan Veličković; Vladimir Šljukić; Ivana Novaković; Valerija Dobričić; Marjan Micev; Predrag Peško

doi:10.2298/VSP180205048E

Keramatollah A Ebrahimi University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Department of Esophageal Surgery, Belgrade, Serbia
Predrag Sabljak University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Department of Esophageal Surgery, Belgrade, Serbia
Aleksandar P Simić University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Department of Esophageal Surgery, Belgrade, Serbia
Ognjan M Skrobić University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Department of Esophageal Surgery, Belgrade, Serbia
Dejan Veličković University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Department of Esophageal Surgery, Belgrade, Serbia
Vladimir Šljukić University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Department of Esophageal Surgery, Belgrade, Serbia
Ivana Novaković University of Belgrade, Faculty of Medicine, Institute for Human Genetics, Belgrade, Serbia
Valerija Dobričić University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Institute of Neurology, Belgrade, Serbia
Marjan Micev University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Department of Digestive Pathology, Belgrade, Serbia
Predrag Peško University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Department of Esophageal Surgery, Belgrade, Serbia

DOI: https://doi.org/10.2298/VSP180205048E

Keywords: gastrointestinal stromal tumors, genes, mutation, digestive system surgical procedures, neoplasm metastasis, prognosis, survival

Abstract

Abstract

Background/Aim. 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 the patients who underwent surgical resection of gastric GIST, but without imatinib mesylate treatment. Methods. Retrospective clinical study included patients who were operated on due to gastric GIST from November 2000 till November 2016. A molecular analysis of paraffin embedded tumor tissue was performed, and the patients with the presence of KIT and PDGFRA mutations were further evaluated, with regard to the pathological tumor stage, disease recurrence and overall survival. Results. Out of 45 patients in total, 43 patients had KIT and PDGFRA mutations, and 2 patients were classified as the wild type GIST. After curative resection, 11 patients were classified as a low risk GIST, 8 as an intermediate risk and 26 as a high risk GIST. The KIT mutations were present in 37 patients, most commonly as deletion in exon 11. The PDGFRA mutations were present in 6 patients. The presence of KIT mutation had a strong statistical correlation with the mitotic index (p = 0.021). After the ten-year follow-up, all patients with the PDGFRA mutations were alive, while those with the KIT mutations had a survival rate of 71% (p = 0.31). Conclusion. The presence of KIT exon 11 deletion in the patients with primarily resected gastric GIST is associated with the higher mitotic index and worse overall survival than those present with the PDGFRA mutations. This results suggest prognostic significance towards more aggressive behaviors.

Author Biographies

Keramatollah A Ebrahimi, University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Department of Esophageal Surgery, Belgrade, Serbia

opšti hirurg na Centru za hirurgiju jednjaka

Klinički asistent na Medicinskom fakultetu, Univerziteta u Beogradu

Predrag Sabljak, University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Department of Esophageal Surgery, Belgrade, Serbia

načelnik V odeljenja, Prve hirurške klinike

Docent na Medicinskom fakultetu Beograd

Marjan Micev, University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Department of Digestive Pathology, Belgrade, Serbia

načelnik odeljenja patologije Klinike za digestivnu hirurgiju

Predrag Peško, University of Belgrade, Faculty of Medicine, Clinical Center of Serbia, First Surgical University Hospital, Department of Esophageal Surgery, Belgrade, Serbia

načelnik centra za hirurgiju jednjaka

redovni profesor na Medicinskom fakultetu

Univerzitet u Beogradu

References

REFERENCES

Søreide K, Sandvik OM, Søreide JA, Giljaca V, Jureckova A, Bulusu VR. Global epidemiology of gastrointestinal stromal tumours (GIST): A systematic review of population-based cohort studies. Cancer Epidemiol 2016; 40: 39–46.

Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 2004; 22(18): 3813–25.

Nilsson B, Bümming P, Meis-Kindblom JM, Odén A, Dortok A, Gustavsson B, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden. Cancer 2005; 103(4): 821–9.

Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 2002; 33(5): 459–65.

Lasota J, Miettinen M. KIT and PDGFRA mutations in ga-strointestinal stromal tumors (GISTs). Semin Diagn Pathol 2006; 23(2): 91–102.

Stenman G, Eriksson A, Claesson-Welsh L. Human PDGFA re-ceptor gene maps to thesame region on chromosome 4 as the KIT oncogene. Genes Chromosomes Cancer 1989; 1(2): 155–8.

Pawson T. Regulation and targets of receptor tyrosine kinases. Eur J Cancer 2002; 38 Suppl 5: S3–10.

Mol CD, Dougan DR, Schneider TR, Skene RJ, Kraus ML, Scheibe DN, et al. Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem 2004; 279(30): 31655-63.

Martín J, Poveda A, Llombart-Bosch A, Ramos R, López-Guerrero JA, García del Muro J, et al. Deletions affecting codons 557-558 of the c-KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors: a study by the Spanish Group for Sarcoma Research (GEIS). J Clin Oncol 2005; 23(25): 6190–8.

Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Jo-seph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003; 299(5607): 708–10.

Lasota J, Dansonka-Mieszkowska A, Sobin LH, Miettinen M. A great majority of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant potential. Lab Invest 2004; 84(7): 874–83.

Baskin Y, Kocal GC, Kucukzeybek BB, Akbarpour M, Kayacik N, Sagol O, et al. PDGFRA and KIT Mutation Status and Its As-sociation With Clinicopathological Properties, Including DOG1. Oncol Res 2016; 24(1): 41–53.

Kim TW, Lee H, Kang YK, Choe MS, Ryu MH, Chang HM, et al. Prognostic significance of c-kit mutation in localized gastroin-testinal stromal tumors. Clin Cancer Res 2004; 10(9): 3076–81.

Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology 2008; 53(3): 245–66.

Daniels M, Lurkin I, Pauli R, Erbstösser E, Hildebrandt U, Hellwig K, et al. Spectrum of KIT/PDGFRA/BRAF mutations and Phosphatidylinositol-3-Kinase pathway gene alterations in gastrointestinal stromal tumors (GIST). Cancer Lett 2011; 312(1): 43–54.

Joensuu H, Rutkowski P, Nishida T, Steigen SE, Brabec P, Plank L, et al. KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence. J Clin Oncol 2015; 33(6): 634–42.

Andersson J, Bümming P, Meis-Kindblom JM, Sihto H, Nupponen N, Joensuu H, et al. Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology 2006; 130(6): 1573–81.

Wardelmann E, Losen I, Hans V, Neidt I, Speidel N, Bierhoff E, et al. Deletion of Trp-557 and Lys-558 in the juxtamembrane domain of the c-kit protooncogene is associated with metastatic behavior of gastrointestinal stromal tumors. Int J Cancer 2003; 106(6): 887–95.

Capelli L, Petracci E, Quagliuolo V, Saragoni L, Colombo P, Morgagni P, et al. Italian Gastric Cancer Research Group (GIRCG). Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients - A GIRCG study. Eur J Surg Oncol 2016; 42(8): 1206–14.

Schaefer IM, Delfs C, Cameron S, Gunawan B, Agaimy A, Ghadimi BM, et al. Chromosomal aberrations in primary PDGFRA-mutated gastrointestinal stromal tumors. Hum Pathol 2014; 45(1): 85–97.

Rossi S, Gasparotto D, Miceli R, Toffolatti L, Gallina G, Scaramel E, et al. KIT, PDGFRA, and BRAF mutational spectrum impacts on the natural history of imatinib-naive localized GIST: a population-based study. Am J Surg Pathol 2015; 39(7): 922–30.