Molecular characterisation of gastrointestinal stromal tumours in a South African population

Abstract

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.

Unraveling the spectrum of KIT mutations in gastrointestinal stromal tumors: An Indian Tertiary Cancer Center Experience

“…The frequency of KIT mutations in our cohort was 70% (70/100) is the highest reported from India comparable to Western data. [ 15 20 21 ] An interesting observation in the present study is the documentation of mutations in exons 13, 17, and simultaneous mutations in exons 11 and 13. The variation in mutations frequency across literature stems from referral center bias, tumor tissue types, methodology, and analysis.…”

Somatic mutational spectrum analysis in a prospective series of 104 gastrointestinal stromal tumors

“…Thus, KIT and PDGFRA mutations are found respectively in 70 and 10% of cases in the USA (59), 70.7 and 20% in France (4), 67.9 and 1% in China (60), and 72.4 and 6.5% in South Africa (61). Notably, the variation of the genotype mainly involves the proportion of PDGFRA-mutated tumors.…”

Gastrointestinal stromal tumours at Inkosi Albert Luthuli Central Hospital from 2005 to 2015

“…12,13,1,4,15,16,17,18 A South African series found c-KIT and PDGFRA mutations in 78.3% of GISTs, while wild-type GIST was found in 21.7% of the population. 19 Immunohistochemical staining for CD117 (KIT immunostaining), DOG1 and CD34, and genetic molecular testing for c-KIT and/or PDGFRA mutations are used to diagnose GIST. 4,8,20 Both CD34 and DOG1 are highly expressed in GIST, and DOG1 immunostaining may be useful for cases that cannot be categorised as GIST based on CD117 immunostaining.…”