Impact of KIT exon 10 M541L allelic variant on the response to imatinib in aggressive fibromatosis: analysis of the desminib series by competitive allele specific Taqman PCR technology

Abstract

BackgroundAggressive fibromatosis (AF) is a rare fibroblastic proliferative disease with a locally aggressive behavior and no distant metastasis, characterized by driver mutations in CTNNB1 or the APC gene. When progressive and/or symptomatic AF is not amenable to local management, a variety of medical treatments may be efficient, including imatinib mesylate. The phase II “Desminib trial” included 40 patients with AF to evaluate the toxicity and efficacy of imatinib resulting in a 65% tumor control rate at 1 year. We investigated a potential predictive value of KIT exon 10 M541L variant (KITL541) on this prospective series.MethodsDNA was extracted in sufficient quantity from 33 patients included in the Desminib trial. The detection of KITL541 was performed by Competitive Allele-Specific Taqman® PCR technology. Chi-2 analyses were performed to search for a correlation between KIT status and tumor response. Progression free (PFS) and overall survival (OS) were compared by log-rank test after Kaplan-Meier analysis.ResultsIn 6 out of 33 cases (18%), the technique failed to determine the mutational status; 5 patients (19%) harboured KITL541 and 22 patients (81%) were classified as KIT wild type. Compared with total cohort, KITL541 frequency did not distinguish between different clinical characteristics. In the KITL541 and the KITWT subgroups, the tumor control rate at 1 year was 100% and 68%, respectively (p = 0.316). The median PFS of patients harboring KITL541 or not is 29.9 and 24.5 months, respectively (p = 0.616), and the median OS is not reached, in any of the groups.ConclusionOur results do not support a predictive effect of KITL541 on the efficacy of imatinib for patients with AF.

Novel pathogenic alterations in pediatric and adult desmoid-type fibromatosis – A systematic analysis of 204 cases

“…The authors describe a positive correlation of CTNNB1 mutational status and progression arrest rate after imatinib treatment, especially in DTF tumors harboring a CTNNB1 S45F alteration which were overrepresented in that study. In accordance with previously published results 30,31 , the known KIT polymorphism M541L was demonstrated in 16% of all analyzed DTF cases. In a prospective series by Dufresne et al, no predictive effect of the M541L variant on the efficacy of imatinib therapy for patients with DTF was seen 30 .…”

“…In accordance with previously published results 30,31 , the known KIT polymorphism M541L was demonstrated in 16% of all analyzed DTF cases. In a prospective series by Dufresne et al, no predictive effect of the M541L variant on the efficacy of imatinib therapy for patients with DTF was seen 30 .…”

Enzymological description of multitemplate PCR—Shrinking amplification bias by optimizing the polymerase–template ratio

“…Minor groove binders (MGB) can specifically block synthesis of a competing template. MGB blockers are usually used to suppress the wild type allele (Dufresne et al, 2014). This approach increases the sensitivity of detection of the rare allele by eliminating amplification of competing template, ensuring that the total primertemplate concentrations are below the limit of possible competition.…”

KIT exon 10 variant (c.1621 A > C) single nucleotide polymorphism as predictor of GIST patient outcome

“…The detection of the SNP was performed by Competitive Allele-Specific Taqman® PCR technology provided by Applied Biosystems®, using the method extensively described by Dufresne et al [ 15 ]. We both performed a CAST®-PCR and a classical sequencing in 13 cases.…”

“…A SNP of KIT exon ten, encoding for the substitution of a methionine in position 541 by a leucine ( KIT L541 ) in the mature KIT protein, has already been reported to be associated with several diseases, including aggressive fibromatosis (AF) [ 13 – 15 ], chronic myelogenous leukemia (CML) [ 16 ], pediatric mastocytosis [ 17 ] and more recently in chronic eosinophilic leukemia [ 18 ]. The potential impact of this variant, observed in about 20 % of the population, on GIST biology, clinical presentation and response to treatment has never been explored.…”