Standard notes github11/12/2022 ![]() Inframe deletions more than 6bp was considered as large deletions and mutations less than 6bp were considered as small deletions.Įxon 11 mutations were grouped and analysed separately as mutually non-exclusive groups: Inframe deletions: codons 557 and 558 (6 bp deletions) in KIT exon 11 are the deletion hot spots in GISTs affecting the regulatory juxtamembrane domain of Kit gene resulting in gain of function mutations ( 18). Samples which were non-amplified, with noise or with non-readable sequences, were repeated once before considering them as uninterpretable.Ĭomplex mutations: complex mutations in which inframe deletions were associated with second mutation within exon 11 and these second mutations were point mutations, insertions and duplications. The dbSNP, COSMIC and Ensemble were referred before considering the abnormal results as ‘novel mutations’. The reference sequence used in this study is KIT (Gene ID 3815). Sequences were analysed using sequence analysis softwares SeqScape® (Applied Biosystems) and Chromas Lite and were compared with the wild-type KIT reference sequence, with the mutations being reported as per the recommendations of the Human Genome Variation Society (HGVS). Purified PCR products were subjected to direct DNA sequencing in both directions using BigDye v3.1 cycle sequencing kit (Applied Biosystems, USA). Besides survival of the entire cohort, we also examined how the codon 557-558 mutation cohort compared against other exon 11 KIT mutants.Īrchived formalin-fixed paraffin-embedded tissues (FFPE) of histologically and immunohistochemically proven GIST tumour samples were used for testing KIT exons 9, 11, 13 and 17 by PCR. With this background, we conducted a retrospective exploratory study to evaluate early outcomes in a purely exon 11 mutated cohort across metastatic and operable subsets, treated with IM. Whether similar findings are observed in the operated setting remains to be seen. However long term results from the BFR14 trial, in advanced inoperable GIST, have confirmed that the codon 557-558 mutation cohort has greater sensitivity to IM, but also develops secondary resistance rapidly compared to other cohorts ( 17). Standard notes github free#Operated patients with mutation in codon 557-558 of exon 11 have lower relapse free survival (RFS) rates compared to alterations in other codons, with a majority of the data emerging from studies in patients not treated with IM ( 15, 16). Increasing research has revealed that the exon 11 mutant subset itself is a heterogeneous cohort in terms of biological behaviour. On the other hand, recommendations for the adjuvant and neoadjuvant treatment of operated GIST rely on the various classifications predicting recurrence, based on size, site and mitotic index, without taking into account tumor genotype ( 6, 12- 14). It is well recognized that the exon 11 and exon 9 activating KIT mutations have differential responses and outcomes with IM in advanced/metastatic GIST, with current recommendations allowing a dose of IM 800 mg daily for exon 9 KIT mutants as opposed to the standard 400 mg daily dose for exon 11 mutants ( 8- 11). Approximately 85% of adult patients with GIST possess gain of function mutations in the KIT (75%) and PDGFRA (10%) genes and these mutations act by activation of KIT signalling pathways ( 5- 7). While the identification of immunoreactivity to CD117 (KIT receptor tyrosine kinase) and DOG1 (Discovered on GIST1) have been established as prerequisites for a pathological diagnosis of GIST ( 5), it is the mutations in the KIT genes or platelet derived growth factor receptor-alpha (PDGFRA) genes that have emerged as the translational link between diagnosis, prognosis and prediction of outcomes for patients with GIST. The introduction of imatinib mesylate (IM) for the treatment of gastrointestinal stromal tumors (GIST) has altered the natural history and treatment paradigms of this previously near fatal disease ( 1- 4). ![]()
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