Molecular characterisation of gastrointestinal stromal tumours in a South African population

Baker,Gillian; Babb,Chantal; Schnugh,Desmond; Nayler,Simon; Louw,Melanie; Goedhals,Jacqueline; Bringuier,Pierre-Paul; Blay,Jean-Yves; Willem,Pascale

doi:10.3892/ol.2012.1013

Molecular characterisation of gastrointestinal stromal tumours in a South African population

Authors:
- Gillian Baker
- Chantal Babb
- Desmond Schnugh
- Simon Nayler
- Melanie Louw
- Jacqueline Goedhals
- Pierre-Paul Bringuier
- Jean-Yves Blay
- Pascale Willem
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Affiliations: Department of Molecular Medicine and Haematology, Faculty of Health Sciences, National Health Laboratory Services and University of the Witwatersrand, Johannesburg, Republic of South Africa, National Cancer Registry and Research, NHLS/MRC Cancer Epidemiology Research Group, National Health Laboratory Services, Johannesburg, Republic of South Africa , Department of Molecular Medicine and Haematology, Faculty of Health Sciences, National Health Laboratory Services and University of the Witwatersrand, Johannesburg, Republic of South Africa, Department of Histopathology, Partner Drs Gritzman and Thatcher, The Wits University Donald Gordon Medical Centre, Johannesburg, Republic of South Africa, Department of Anatomical Pathology, National Health Laboratory Service and University of Pretoria, Tshwane, Republic of South Africa, Department of Anatomical Pathology, Faculty of Health Sciences, National Health Laboratory Service and University of the Free State, Bloemfontein, Republic of South Africa, Department of Pathology, Edouard Herriot Hospital and University of Lyon, Lyon, France, Department of Medical Oncology, Center Leon Berard, University Claude Bernard, Lyon, France
Published online on: November 5, 2012 https://doi.org/10.3892/ol.2012.1013
Pages: 155-160

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Abstract

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the digestive tract. Pathogenesis is linked to activating mutations identified in two proto-oncogenes, v-kit Hardy/Zuckerman 4 feline sarcoma viral oncogene homologue KIT (KIT) and the platelet-derived growth factor α (PDGFRα). In addition, these mutations affect response to treatment with tyrosine kinase inhibitors. In the present study, we report on the molecular characterisation of GISTs in the South African population. Tumour DNA was extracted from 46 GIST samples, followed by cycle sequencing of KIT exons 11, 13 and 17 and PDGFRα exons 12, 14 and 18. Fragment length analysis was used to detect a 6-bp duplication in KIT exon 9. Wild-type duplications were analysed further by PCR and sequencing of additional KIT and PDGFRα exons was performed. Overall, 78.3% of the samples had a mutation in KIT or PDGFRα. Of these, mutations were detected in KIT exon 11 (88.9%), PDGFRα exon 18 (8.3%) and KIT exon 9 (2.8%). Mutations varied from simple substitutions and duplications to large deletions (some with nucleotide insertions) resulting in missense mutations. In addition, seven single nucleotide polymorphisms were detected in 17 patients, one of which appears novel. The incidence of mutations in KIT exon 11 and PDGFRα exon 18 is consistent with the literature, however, the low incidence of KIT exon 9 mutations detected was unexpected. In contrast to previous western and Asian studies, this mutation appears to be rare in the South African population. The present study contributes to the molecular understanding of GISTs in the South African population.

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1	Bachet JP and Emile JF: Diagnostic criteria, specific mutations and genetic predisposition in gastrointestinal stromal tumors. Appl Clin Genet. 3:85–101. 2010.PubMed/NCBI
2	Blay JY and Reichardt P: Advanced gastrointestinal stomal tumour in Europe: a review of updated treatment recommendations. Expert Rev Anticancer Ther. 9:1–8. 2009.PubMed/NCBI
3	Gupta P, Tewari M and Shukla HS: Gastrointestinal stromal tumor. Surg Oncol. 17:129–138. 2008. View Article : Google Scholar
4	Hirota S, Isozaki K, Moriyama Y, et al: Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 279:577–580. 1998. View Article : Google Scholar : PubMed/NCBI
5	Heinrich MC, Corless CL, Duensing A, et al: PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 299:708–710. 2003. View Article : Google Scholar : PubMed/NCBI
6	Stenman G, Eriksson A and Claesson-Welsh L: Human PDGFA receptor gene maps to the same region on chromosome 4 as the KIT oncogene. Genes Chromosomes Cancer. 1:155–158. 1989. View Article : Google Scholar : PubMed/NCBI
7	Lasota J and Miettinen M: Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 53:245–266. 2008. View Article : Google Scholar : PubMed/NCBI
8	Corless CL, Fletcher JA and Heinrich MC: Biology of gastrointestinal tumors. J Clin Oncol. 22:3813–3825. 2004. View Article : Google Scholar : PubMed/NCBI
9	Corless C, Schroeder A, Griffith D, et al: PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 23:5357–5364. 2005. View Article : Google Scholar : PubMed/NCBI
10	Cassier PA and Blay JY: Molecular response prediction in gastrointestinal stromal tumors. Target Oncol. 5:29–37. 2010. View Article : Google Scholar : PubMed/NCBI
11	Blay JY: A decade of tyrosine kinase inhibitor therapy: Historical and current perspectives on targeted therapy for GIST. Cancer Treat Rev. 37:373–384. 2011. View Article : Google Scholar : PubMed/NCBI
12	Demetri GD, von Mehren M, Antonescu CR, et al: NCCN Task force report: Update on the management of patients with gastrointestinal stromal tumours. J Natl Compr Canc Netw. 8:S1–41. 2010.PubMed/NCBI
13	Mol CD, Dougan DR, Schneider TR, et al: Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem. 279:31655–31663. 2004. View Article : Google Scholar : PubMed/NCBI
14	Babb C, Schnugh D, Louw M, et al: Getting the gist: what is the importance of molecular genetics in gastro-intestinal stromal tumours (GIST). S Afr Gastroenterol Rev. 8:4–5. 2010.
15	Heinrich MC, Owzar K, Corless CL, et al: Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 26:5360–5367. 2008.
16	Yuzawa S, Opatowsky Y, Zhang Z, Mandiyan V, Lax I and Schlessinger J: Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell. 130:323–334. 2007. View Article : Google Scholar : PubMed/NCBI
17	Abdulkareem FB, Rotimi O, Elesha SO and Banjo AA: Immunophenotyping of gastrointestinal mesenchymal tumours in Lagos, Nigeria. West Afr J Med. 28:358–362. 2009.PubMed/NCBI
18	Hartley RJ, Becker JHR, Van Der Walt H and Luyhengo T: Gastro-intestinal stromal tumours (GISTs) - the Pretoria experience and a literature review. S Afr J Surg. 49:128–131. 2011.PubMed/NCBI
19	Tran T, Davila JA and El-Serag HB: The epidemiology of malignant gastrointestinal stromal tumors: an analysis of 1,458 cases from 1992 to 2000. Am J Gastroenterol. 100:162–168. 2005. View Article : Google Scholar : PubMed/NCBI
20	Tzen CY, Wang MN and Mau BL: Spectrum and prognostication of KIT and PDGFRA mutation in gastrointestinal stromal tumors. Eur J Surg Oncol. 34:563–568. 2008. View Article : Google Scholar : PubMed/NCBI
21	Agaram NP, Baren A, Arkun K, Dematteo NP, Besmer P and Antonescu CR: Comparative ultrastructural analysis and KIT/PDGFRA genotype in 125 gastrointestinal stromal tumors. Ultrastruct Pathol. 30:443–452. 2006. View Article : Google Scholar : PubMed/NCBI
22	Miettinen M, Sobin LH and Lasota J: Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 29:52–68. 2005. View Article : Google Scholar : PubMed/NCBI
23	Miettinen M, Makhlouf H, Sobin LH and Lasota J: Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol. 30:477–489. 2006. View Article : Google Scholar
24	Debiec-Rychter M, Dumez H, Judson I, et al: Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 40:689. 2004. View Article : Google Scholar
25	Debiec-Rychter M, Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 42:1093–1103. 2006. View Article : Google Scholar : PubMed/NCBI
26	Andersson J, Bumming P, Meis-Kindblom JM, et al: Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology. 130:1573–1581. 2006. View Article : Google Scholar : PubMed/NCBI
27	Martín J, Poveda A, Llombart-Bosch A, 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. 23:6190–6198. 2005.
28	Yeh CN, Chen TW, Lee HL, et al: Kinase mutations and imatinib mesylate response for 64 Taiwanese with advanced GIST: preliminary experience from Chang Gung Memorial Hospital. Ann Surg Oncol. 14:1123–1128. 2007. View Article : Google Scholar : PubMed/NCBI
29	He HY, Fang WG, Zhong HH, et al: Status and clinical implication of c-KIT and PDGFRA mutations in 165 cases of gastrointestinal stromal tumor (GIST). Zhonghua Bing Li Xue Za Zhi. 35:262–266. 2006.(In Chinese).
30	Sakurai S, Fukasawa T, Chong JM, Tonaka A and Fukayama M: C-kit gene abnormalities in gastrointestinal stromal tumors (tumors of interstitial cells of Cajal). Jpn J Cancer Res. 90:1321–1328. 1999. View Article : Google Scholar : PubMed/NCBI
31	Sakurai S, Oguni O, Hironaka M, Fukayama M, Morinaga S and Saito K: Mutations in c-kit gene exons 9 and 13 in gastrointestinal stromal tumors among Japanese. Jpn J Cancer Res. 92:494–498. 2001. View Article : Google Scholar : PubMed/NCBI
32	Hirota S, Ohashi A, Nishida T, Isozaki K, Kinoshita K, Shinomura Y and Kitamura O: Gain-of-function mutations of platelet-derived growth factor receptor α gene in gastrointestinal stromal tumors. Gastroenterology. 125:660–667. 2003.
33	Braggio DA, Braggio E, Small IA, et al: The profile of platelet-derived growth factor receptor alpha (PDGFRA) gene alterations in GIST patients (pts) from Brazil. J Clin Oncol. 26:105612008.
34	Campbell MC and Tishkoff SA: African genetic diversity: implications for human demographic history, modern human origins and complex disease mapping. Annu Rev Genomics Hum Genet. 9:303–333. 2008. View Article : Google Scholar