Prognostic relevance of genetic aberrations in gastrointestinal stromal tumors.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 49-49
Author(s):  
N. N. Mazurenko ◽  
I. S. Beliakov ◽  
I. V. Tsyganova ◽  
E. M. Bardina ◽  
O. A. Anurova ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Point Mutation ◽  
Prognostic Significance ◽  
Specific Gene ◽  
Wild Type ◽  
Kit Mutation ◽  
Genetic Aberrations ◽  
Pdgfra Mutation ◽  
Prognostic Relevance ◽  
Exon 11

49 Background: Gastrointestinal stromal tumours (GISTs) contain oncogenic KIT or PDGFRA tyrosine kinase (TK) mutations leading to disturbance of downstream signaling pathways that contribute to GIST pathogenesis. Additional genetic aberrations were found in GISTs, demonstrating the involvement of other genes important in tumor progression. The aim of the study was to evaluate the prognostic relevance of different TK mutations in GISTs and to analyze the additional genetic aberrations in GISTs according to mutational status. Methods: 180 GIST patients were examined for KIT (9, 11, 13, 17 exons) and PDGFRA mutations (12, 14, 18 exons) by direct sequencing of DNA obtained from microdissected tumor sections. Tumor tissue DNA from 44 GISTs patients was screened for loss of heterozygosity (LOH) at 11 microsatellite loci on 1p, 9p, 14q, 15q and 22q arms. Results: KIT and PDGFRA mutations were identified in 76.1% and 10% of GISTs, respectively. 13.9% GISTs had no mutations (wild type). Most of KIT mutations were located in exon 11 (65%) and exon 9 (9.4%). Prognostic significance of TK mutations was evaluated. There was a trend of better survival for patients with PDGFRA mutation then with KIT mutation or wild type GISTs. The higher overall survival prior to target therapy was shown for patients with duplication or point mutation in KIT exon 11 in comparison to exon 11 deletion. Analysis of LOH revealed allelic deletions in 85% of GISTs, more frequently at 14q arm. There was a different LOH pattern in subgroups of GISTs. GISTs with PDGFRA mutation and with KIT exon 11 point mutation had LOH at 14q, while GISTs with KIT exon 11 deletions revealed high LOH frequency also on 22q, 15q and 1p arms. LOH in wild type GISTs occurred on all chromosomes with low frequency. LOH on 9p was found exclusively in metastatic and recurrent GISTs. Specific gene loci of frequent LOH were identified on 9p, 15q and 22q that may be contributed to GIST progression. Conclusions: Specific mutations are associated with GISTs prognosis. Tumors with point mutations and duplications in KIT exon 11 are associated with a better survival then GISTs with other KIT mutations. Specific pattern of allelic deletions was identified in subgroups of GISTs according to type of mutation and tumor progression. No significant financial relationships to disclose.

ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate (IM) for primary and recurrent operable malignant GIST: Imaging findings and correlation with genotype and GLUT4 expression

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10552-10552
Author(s):  
A. D. Van den Abbeele ◽  
C. Gatsonis ◽  
D. J. de Vries ◽  
Y. Melenevsky ◽  
A. Szot Barnes ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Fdg Pet ◽  
Metabolic Response ◽  
Objective Response ◽  
Wild Type ◽  
Genotype 4 ◽  
Mutation Status ◽  
Pdgfra Mutation ◽  
Glut4 Expression ◽  
Exon 11

10552 Background: IM has improved the treatment of GIST patients (pts), but few achieve objective response despite significant clinical benefit. Imaging of tumor metabolism may provide earlier assessment of therapeutic response. In this study, FDG-PET metabolic response (MR) was compared with RECIST, GLUT4 expression, and KIT/PDGFRA mutation status. Methods: FDG-PET was done at baseline, 1–7 days, and 4 or 8 weeks (wk) after IM initiation. Best objective response was defined by RECIST. Immunohistochemical (IHC) tumor GLUT4 expression and mutation analyses were done at baseline and/or surgery. Background-subtracted SUVmax was measured in all lesions and summed; MR based on EORTC criteria was compared to RECIST, GLUT4 expression, and KIT/PDGFRA mutation status. Results: FDG-PET showed high tumor glycolytic activity at baseline (mean SUVmax = 14.2, range: 1.3–53.2), decreasing after 1 wk of IM (5.5, range: 0.5–47.7, p < 0.001, n = 44), and again prior to surgery (3.0, range: 0.5–36.1, p < 0.001, n = 40). FDG-PET response at wk 1 was 3 complete MR (CMR), 33 partial MR (PMR), 6 stable metabolic disease (SMD), and 2 progressive metabolic disease (PMD). Prior to surgery, FDG-PET response was 3 CMR, 33 PMR, 4 SMD, and no PMD. For 39 pts, RECIST best response was 2 PR, 36 SD, and 1 PD. GLUT4 expression decreased in 19 pts with PMR, and 3 with SMD. Among 12 pts with exon 11 mutation, 11 had PMR, 1 SMD; among 5 pts with wild-type genotype, 4 had PMR, and 1 SMD. Conclusions: After IM initiation, MR by FDG-PET was documented earlier (1–7 days), and was of much greater magnitude (36/40) than that documented by RECIST (2/39). IHC data suggest that: (1) GLUT4 plays a role in FDG uptake in GIST; (2) GLUT4 decreases in most pts with PMR; and, (3) the biologic action of IM interacts with glycolysis and GLUT4 expression. No difference in PMR was seen in pts with exon 11 vs. wild type mutations. [Table: see text]

scholarly journals Significance of KIT and PDGFRA mutations in gastric gist imatinib - naive surgically treated patients

2019 ◽  
Vol 76 (12) ◽  
pp. 1268-1273
Author(s):  
Keramatollah Ebrahimi ◽  
Predrag Sabljak ◽  
Aleksandar Simic ◽  
Ognjan Skrobic ◽  
Dejan Velickovic ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mitotic Index ◽  
Prognostic Significance ◽  
Growth Factor Receptor ◽  
Tumor Stage ◽  
Disease Recurrence ◽  
Gastric Gist ◽  
Kit Mutation ◽  
Retrospective Clinical Study ◽  
Exon 11

Background/Aim. KIT (KIT proto-oncogene receptor tyrosine kinase) and PDGFRA (platelet-derived growth factor receptor alpha) gene mutations represent major molecular forces inside the gastrointestinal stromal tumors (GIST). Aim of this study was to evaluate these mutations in the patients who underwent surgical resection of gastric GIST, but without imatinib mesylate treatment. Methods. Retrospective clinical study included patients who were operated on due to gastric GIST from November 2000 till November 2016. A molecular analysis of paraffin embedded tumor tissue was performed, and the patients with the presence of KIT and PDGFRA mutations were further evaluated, with regard to the pathological tumor stage, disease recurrence and overall survival. Results. Out of 45 patients in total, 43 patients had KIT and PDGFRA mutations, and 2 patients were classified as the wild type GIST. After curative resection, 11 patients were classified as a low risk GIST, 8 as an intermediate risk and 26 as a high risk GIST. The KIT mutations were present in 37 patients, most commonly as deletion in exon 11. The PDGFRA mutations were present in 6 patients. The presence of KIT mutation had a strong statistical correlation with the mitotic index (p = 0.021). After the ten-year follow-up, all patients with the PDGFRA mutations were alive, while those with the KIT mutations had a survival rate of 71% (p = 0.31). Conclusion. The presence of KIT exon 11 deletion in the patients with primarily resected gastric GIST is associated with the higher mitotic index and worse overall survival than those present with the PDGFRA mutations. This results suggest prognostic significance towards more aggressive behaviors.

scholarly journals KIT Mutation Incidence and Pattern of Melanoma in Central Europe

2019 ◽  
Vol 26 (1) ◽  
pp. 17-22 ◽  
Author(s):  
V. Doma ◽  
T. Barbai ◽  
M.-A. Beleaua ◽  
I. Kovalszky ◽  
E. Rásó ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Cutaneous Melanoma ◽  
Mutation Frequency ◽  
Mucosal Melanoma ◽  
Wild Type ◽  
Mutation Site ◽  
Kit Mutation ◽  
Central European ◽  
Exon 9 ◽  
Exon 11

AbstractData on the KIT mutation rate in melanoma in the central European region is missing. Accordingly, in a cohort of 79 BRAF/NRAS double wild type cutaneous melanoma and 17 mucosal melanoma KIT mutation was assessed by Sanger sequencing of exons 9,11,13,17 and 18. In this cutaneous melanoma cohort KIT mutation frequency was found to be 34/79 (43.04%) with a significantly higher rate in acrolentiginous melanoma (ALM) as compared to UV-induced common variants (20/34, 58.8% versus 14/45, 31.1%, p = 0.014). In the double wild type mucosal melanoma cohort the KIT mutation frequency was found to be comparable (41.2%). The actual frequency of KIT mutation in the original 227 patient cutaneous melanoma cohort was 34/227, 14.9%. Exon 11 was the most frequent mutation site (44.7%) followed by exon 9 (21.1%) equally characterizing UV-induced common histotypes and ALM tumors. In mucosal melanoma exon 9 was the most frequently involved exon followed by exon 13 and 17. KIT mutation hotspots were identified in exon 9 (c482/491/492), in exon 11 (c559,c572, c570), in exon 13 (c642), in exon 17 (c822) and in exon 18 (c853). The relatively high KIT mutation rate in cutaneous melanoma in this central-European cohort justifies regular testing of this molecular target in this entity, not only in mucosal variants.

scholarly journals Transcriptome and metabolome profiling provide insights into molecular mechanism of pseudostem elongation in banana

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Guiming Deng ◽  
Fangcheng Bi ◽  
Jing Liu ◽  
Weidi He ◽  
Chunyu Li ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cell Elongation ◽  
Molecular Mechanisms ◽  
Specific Gene ◽  
Wild Type ◽  
Banana Plant ◽  
Cell Wall Modification ◽  
Dwarf Cultivar ◽  
Important Trait ◽  
Metabolome Profiling

AbstractBackgroundBanana plant height is an important trait for horticultural practices and semi-dwarf cultivars show better resistance to damages by wind and rain. However, the molecular mechanisms controlling the pseudostem height remain poorly understood. Herein, we studied the molecular changes in the pseudostem of a semi-dwarf banana mutant Aifen No. 1 (Musaspp. Pisang Awak sub-group ABB) as compared to its wild-type dwarf cultivar using a combined transcriptome and metabolome approach.ResultsA total of 127 differentially expressed genes and 48 differentially accumulated metabolites were detected between the mutant and its wild type. Metabolites belonging to amino acid and its derivatives, flavonoids, lignans, coumarins, organic acids, and phenolic acids were up-regulated in the mutant. The transcriptome analysis showed the differential regulation of genes related to the gibberellin pathway, auxin transport, cell elongation, and cell wall modification. Based on the regulation of gibberellin and associated pathway-related genes, we discussed the involvement of gibberellins in pseudostem elongation in the mutant banana. Genes and metabolites associated with cell wall were explored and their involvement in cell extension is discussed.ConclusionsThe results suggest that gibberellins and associated pathways are possibly developing the observed semi-dwarf pseudostem phenotype together with cell elongation and cell wall modification. The findings increase the understanding of the mechanisms underlying banana stem height and provide new clues for further dissection of specific gene functions.

scholarly journals Occurrence of Repeat Induced Point Mutation in Long Segmental Duplications of Neurospora

Genetics ◽  
1997 ◽  
Vol 147 (1) ◽  
pp. 125-136 ◽  
Author(s):  
David D Perkins ◽  
Brian S Margolin ◽  
Eric U Selker ◽  
S D Haedo
Keyword(s):  
Point Mutation ◽  
Sexual Cycle ◽  
Segmental Duplications ◽  
Wild Type ◽  
Single Chain ◽  
Base Pairs ◽  
Gene Size ◽  
Type Gene ◽  
Repeat Induced Point Mutation

Abstract Previous studies of repeat induced point mutation (RIP) have typically involved gene-size duplications resulting from insertion of transforming DNA at ectopic chromosomal positions. To ascertain whether genes in larger duplications are subject to RIP, progeny were examined from crosses heterozygous for long segmental duplications obtained using insertional or quasiterminal translocations. Of 17 distinct mutations from crossing 11 different duplications, 13 mapped within the segment that was duplicated in the parent, one was closely linked, and three were unlinked. Half of the mutations in duplicated segments were at previously unknown loci. The mutations were recessive and were expressed both in haploid and in duplication progeny from Duplication × Normal, suggesting that both copies of the wild-type gene had undergone RIP. Seven transition mutations characteristic of RIP were found in 395 base pairs (bp) examined in one ro-11 allele from these crosses and three were found in ~750 bp of another. A single chain-terminating C to T mutation was found in 800 bp of arg-6. RIP is thus responsible. These results are consistent with the idea that the impaired fertility that is characteristic of segmental duplications is due to inactivation by RIP of genes needed for progression through the sexual cycle.

scholarly journals Prognostic Impacts of D816V KIT Mutation and Peri-Transplant RUNX1–RUNX1T1 MRD Monitoring on Acute Myeloid Leukemia with RUNX1–RUNX1T1

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 336
Author(s):  
Byung-Sik Cho ◽  
Gi-June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
Young-Woo Jeon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Poor Survival ◽  
Hematopoietic Stem ◽  
Kit Mutation ◽  
Time Points ◽  
Post Transplant ◽  
Acute Myeloid

The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, n = 112) or autologous HSCT (Auto-HSCT, n = 54). D816V KIT mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant RUNX1–RUNX1T1 MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V KIT mutation and pre-transplant RUNX1–RUNX1T1 MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V KIT mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V KIT mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V KIT mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V KIT mutation and RUNX1–RUNX1T1 MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches.

scholarly journals Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor

2008 ◽  
Vol 26 (33) ◽  
pp. 5352-5359 ◽  
Author(s):  
Michael C. Heinrich ◽  
Robert G. Maki ◽  
Christopher L. Corless ◽  
Cristina R. Antonescu ◽  
Amy Harlow ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Clinical Results ◽  
Clinical Activity ◽  
Wild Type ◽  
Mutational Status ◽  
Imatinib Resistant ◽  
Exon 9 ◽  
Exon 11 ◽  
The Impact

PurposeMost gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor α (PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity.Patients and MethodsTumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic, imatinib-resistant/intolerant GIST. KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy. Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity.ResultsClinical benefit (partial response or stable disease for ≥ 6 months) with sunitinib was observed for the three most common primary GIST genotypes: KIT exon 9 (58%), KIT exon 11 (34%), and wild-type KIT/PDGFRA (56%). Progression-free survival (PFS) was significantly longer for patients with primary KIT exon 9 mutations (P = .0005) or with a wild-type genotype (P = .0356) than for those with KIT exon 11 mutations. The same pattern was observed for overall survival (OS). PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations (which involve the KIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the KIT activation loop). Biochemical profiling studies confirmed the clinical results.ConclusionThe clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma

Blood ◽  
2014 ◽  
Vol 123 (26) ◽  
pp. 4120-4131 ◽  
Author(s):  
Aldo M. Roccaro ◽  
Antonio Sacco ◽  
Cristina Jimenez ◽  
Patricia Maiso ◽  
Michele Moschetta ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Driver Mutation ◽  
Lymphoplasmacytic Lymphoma ◽  
Wild Type ◽  
Key Points ◽  
Activating Mutation

Key Points C1013G/CXCR4 acts as an activating mutation in WM leading to enhanced tumor growth, and as an inducer of drug resistance. BMS936564/MDX1338, a novel anti-CXCR4 moAb, successfully targets WM cells, either C1013G/CXCR4 mutated or wild-type.

scholarly journals Increase in Zucchini yellow mosaic virus Symptom Severity in Tolerant Zucchini Cultivars Is Related to a Point Mutation in P3 Protein and Is Associated with a Loss of Relative Fitness on Susceptible Plants

2003 ◽  
Vol 93 (12) ◽  
pp. 1478-1484 ◽  
Author(s):  
C. Desbiez ◽  
A. Gal-On ◽  
M. Girard ◽  
C. Wipf-Scheibel ◽  
H. Lecoq
Keyword(s):  
Mosaic Virus ◽  
Point Mutation ◽  
Zucchini Yellow Mosaic Virus ◽  
Genetic Load ◽  
Yellow Mosaic Virus ◽  
Relative Fitness ◽  
Interspecific Crosses ◽  
Mixed Infections ◽  
Wild Type ◽  
Sequence Comparisons

Zucchini yellow mosaic virus (ZYMV, Potyvirus) is a very damaging cucurbit virus worldwide. Interspecific crosses with resistant Cucurbita moschata have led to the release of “resistant” zucchini squash (C. pepo) F1 hybrids. However, although the resistance is almost complete in C. moschata, the commercial C. pepo hybrids are only tolerant. ZYMV evolution toward increased aggressiveness on tolerant hybrids was observed in the field and was obtained experimentally. Sequence comparisons and recombination experiments revealed that a point mutation in the P3 protein of ZYMV was enough to induce tolerance breaking. Competition experiments were performed between quasi-isogenic wild-type, and aggressive variants of ZYMV distinguished by monoclonal antibodies. The aggressive mutants were more fit than wild-type strains in mixed infections of tolerant zucchini, but they presented a drastic fitness loss in mixed infections of susceptible zucchini or melon. Thus, the ability to induce severe symptoms in tolerant zucchini is related to a genetic load in susceptible zucchini, but also on other susceptible hosts. This represents the first quantitative study of the fitness cost associated with tolerance breaking for a plant virus. Thus, although easily broken, the tolerance might prove durable in some conditions if the aggressive variants are counterselected in susceptible crops.

scholarly journals Functional Promiscuity of Gene Regulation by Serpentine Receptors in Dictyostelium discoideum

1998 ◽  
Vol 18 (10) ◽  
pp. 5744-5749 ◽  
Author(s):  
Irene Verkerke-Van Wijk ◽  
Ji-Yun Kim ◽  
Raymond Brandt ◽  
Peter N. Devreotes ◽  
Pauline Schaap
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Dictyostelium Discoideum ◽  
Developmental Regulation ◽  
Mutant Cell ◽  
Gene Induction ◽  
Specific Gene ◽  
Wild Type ◽  
Animal Development ◽  
Camp Stimulation

ABSTRACT Serpentine receptors such as smoothened and frizzled play important roles in cell fate determination during animal development. InDictyostelium discoideum, four serpentine cyclic AMP (cAMP) receptors (cARs) regulate expression of multiple classes of developmental genes. To understand their function, it is essential to know whether each cAR is coupled to a specific gene regulatory pathway or whether specificity results from the different developmental regulation of individual cARs. To distinguish between these possibilities, we measured gene induction in car1 car3 double mutant cell lines that express equal levels of either cAR1, cAR2, or cAR3 under a constitutive promoter. We found that all cARs efficiently mediate both aggregative gene induction by cAMP pulses and induction of postaggregative and prespore genes by persistent cAMP stimulation. Two exceptions to this functional promiscuity were observed. (i) Only cAR1 can mediate adenosine inhibition of cAMP-induced prespore gene expression, a phenomenon that was found earlier in wild-type cells. cAR1’s mediation of adenosine inhibition suggests that cAR1 normally mediates prespore gene induction. (ii) Only cAR2 allows entry into the prestalk pathway. Prestalk gene expression is induced by differentiation-inducing factor (DIF) but only after cells have been prestimulated with cAMP. We found that DIF-induced prestalk gene expression is 10 times higher in constitutive cAR2 expressors than in constitutive cAR1 or cAR3 expressors (which still have endogenous cAR2), suggesting that cAR2 mediates induction of DIF competence. Since in wild-type slugs cAR2 is expressed only in anterior cells, this could explain the so far puzzling observations that prestalk cells differentiate at the anterior region but that DIF levels are actually higher at the posterior region. After the initial induction of DIF competence, cAMP becomes a repressor of prestalk gene expression. This function can again be mediated by cAR1, cAR2, and cAR3.

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