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

Abstract

BackgroundTumor genotype plays a crucial role in clinical management of GIST. Whether genetic polymorphism of KIT may influence GIST patient outcome is unclear.MethodsWe investigated the biological and clinical significance of the presence of KIT exon 10 variant (c.1621 A > C), KITL541, in a transfected cell line (3 T3 L541) and in two retrospectively collected series of 109 GIST patients in total. The control group consisted of 60 healthy donors collected at the French department of blood transfusion.ResultsIn the 3 T3 L541 cell line, KITL541 protein exhibited a spontaneous phosphorylation status comparable to that of wild-type KIT but displayed a phosphorylation pattern of AKT and ERK1/2 that was found similar to that of the classical mutated forms of the KIT receptor. Of 109 patients enrolled in this retrospective translational research study, 24 (22 %) harboured KITL541, similarly to the control group of healthy donors (n = 10 of 60, 17 %). A higher prevalence of the variant KITL541 was observed in patients with metastatic status at diagnosis (KITL541 correlated nine of 22 versus 15 of 87, p = 0.02). In addition, patients with KITL541 and localized GIST had a higher rate of relapse at 5 years and lower relapse free survival at 5 years in univariate, as well as in multivariate analysis. Response rate and duration of response to imatinib was similar in KITL541 and KITM541 patients.ConclusionKITL541 genotype is associated with a higher risk of metastasis at diagnosis and a higher risk of relapse in GIST patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1817-5) contains supplementary material, which is available to authorized users.

Stable expansion of high‐grade serous ovarian cancer organoids requires a low‐Wnt environment

“…All of the TP53 mutations in the organoid cultures were homozygous (> 0.9 allele frequency), yet diverse with respect to mutation type (missense, nonsense, frame‐shift, or splice variant mutations). In addition to somatic mutations with proven tumorigenic potential, a number of known variant alleles were identified, including ROCK2 (c.1292C>A), KIT (c.1621A>C), MLH1 (c.655A>G), and MSH6 (c.472C>T) which could potentially influence the malignant phenotype (Kalender et al , ; Nakamura et al , ; Brahmi et al , ). Apart from TP53 , MLH1, and MSH6 , we also found point mutations in other genes with functions in DNA repair and chromosome stability, including ATM (c.4534G>A), ATR (c.1517A>G), BRIP1 (c.254T>A), and FANCA (c.1238G>T).…”

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas

“…In this study, the germline KIT p.(Met541Leu) variant was found in 9% of TETs. To date, Met541Leu has mostly been reported in GISTs, in which it is associated with an increased risk of tumour progression and dissemination [ 81 , 82 , 83 ]. Using transfected cell lines, Brahmi et al found that KIT p.(Met541Leu) induced mutant-like intracellular signalling in the presence of stem cell factor [ 81 ].…”

Broad spectrum of regorafenib activity on mutant KIT and absence of clonal selection in gastrointestinal stromal tumor (GIST): correlative analysis from the GRID trial

“…M541L is the most common KIT polymorphism known (rs3822214) with a minor allele frequency of 0.08 in the gnomAD database ( https://gnomad.broadinstitute.org/ ), is classified as benign/likely benign on ClinVar ( www.ncbi.nlm.nih.gov/clinvar/ ), and has been described in the literature as a driver of pediatric mastocytosis [ 25 ]. In patients with GIST, the KIT M541L polymorphism has been shown to be associated with a higher risk of metastasis at diagnosis, and with a higher risk of relapse [ 26 , 27 ]. A higher prevalence of this genotype has also been seen in the disease of higher-risk patients (with tumor duality, un-resectable and/or locally advanced disease, in addition to metastases at diagnosis) compared with patients with localized GIST [ 27 ].…”