Molecular characterization of an Italian series of sporadic GISTs

Origone, Paola; Gargiulo, Sara; Mastracci, Luca; Ballestrero, Alberto; Battistuzzi, Linda; Casella, Claudio; Comandini, Danila; Cusano, Roberto; Tos, Angelo Paolo Dei; Fiocca, Roberto; Garuti, Anna; Ghiorzo, Paola; Martinuzzi, Claudia; Toffolatti, Luisa; Scarrà, Giovanna Bianchi

doi:10.1007/s10120-012-0213-y

Cited by 18 publications

(10 citation statements)

References 20 publications

(27 reference statements)

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“…Mutation analysis performed on Slovenian patients with GIST has confirmed a high degree of mutation heterogeneity in KIT and PDGFRA genes, as reported in previous studies (24)(25)(26)(27)(28)(29). With direct Sanger sequencing of exons 9, 11, 13 and 17 of KIT gene and exons 12, 14 and 18 of PDGFRA gene, a total of 49 different alterations were detected.…”

Section: Discussionsupporting

confidence: 78%

“…With direct Sanger sequencing of exons 9, 11, 13 and 17 of KIT gene and exons 12, 14 and 18 of PDGFRA gene, a total of 49 different alterations were detected. In the present study, the overall mutation rate was 88.5%, which was slightly higher than in a study from Italy (80%), yet comparable to frequencies observed in studies from Germany (86.1%) and Poland (85.1%), a French population-based study (KIT, 82.8%; PDGFRA, 2.1%), and in two phase III clinical trials that enrolled patients with metastatic GIST from the European Organisation for Research and Treatment of Cancer (KIT, 86.2%; PDGFRA, 1.6%) and Cancer and Leukemia Group B (KIT, 84.6%; PDGFRA, 2.65%) (24)(25)(26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

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Mutational spectrum and classification of novel mutations in patients with metastatic gastrointestinal stromal tumours

et al. 2020

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In total, ~85% of malignant gastrointestinal stromal tumours (GISTs) harbour activating mutations in one of the genes KIT or PDGFRA, while 10-15% of all GISTs have no detectable KIT or PDGFRA mutations, but could have alterations in genes of the succinate dehydrogenase complex or in BRAF, PIK3CA or rarely RAS family genes. The clinical benefit of tyrosine kinase inhibitors, such as imatinib, depends on the GIST genotype, therefore molecular characterization of GIST has a crucial role in overall management of GIST. The aim of the present study was to molecularly characterize a cohort of 70 patients with metastatic GISTs from the Slovenian Cancer Registry (National Cancer Registry) treated between January 2002 and December 2011. Exons 9, 11, 13 and 17 of the KIT gene and exons 12, 14 and 18 of the PDGFRA gene were analysed by direct Sanger sequencing. All KIT/PDGFRA wild-type GISTs were tested for the presence of mutations in hot spot regions of KRAS, NRAS, BRAF, PIK3CA and AKT1 genes. Novel variants were characterized and classified using Cancer Genome Interpreter and according to The American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. In total, 60 (85.7%) patients had mutations in KIT and 2 (2.9%) in PDGFRA. Whereas, 8 (11.4%) patients with GIST had no mutation in either of the analysed genes. The majority of GIST cases (n=52) had a mutation in KIT exon 11, where 40 different mutations were detected. Eight of the variants were novel: c.1652_1672del, c.1653_1660delinsAA, c.1665_1672delinsCC, c.1668_1686del, c.1676_1720del, c.1715_1756dup, c.1721_1765dup, and c.1722_1766dup. Mutation frequencies of KIT and PDGFRA genes observed in Slovenian patients are comparable with those in other European populations. In the present group of patients analysed, the most frequently mutated region was exon 11 in the KIT gene, responsible for coding juxtamembrane domain of KIT protein. In this region, eight novel mutations were identified and classified as likely pathogenic driver variants. In addition, the present study identified 6 patients with secondary KIT mutation and 1 patient with double mutant GIST, who had two different mutations in PDGFRA exon 14.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Mutational spectrum and classification of novel mutations in patients with metastatic gastrointestinal stromal tumours

et al. 2020

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“…A recent paper by Lasota et al reported about the absence of KRAS mutations in a large cohort of GISTs (n =514) [3] which, to the best of our knowledge, constitutes by itself about 60 % of cases so far studied for this molecular alteration [4][5][6][7]. Thus, considering the cumulative evidence produced so far, the actual possible prevalence of KRAS mutations in GISTs seems much lower than the one we hypothesized, possibly approaching 0.3 %.…”

mentioning

confidence: 50%

On the prevalence of KRAS mutations in GISTs

2013

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Dear Editor, In our commentary entitled "GISTogram: a graphic presentation of the growing GIST complexity," recently published in Virchows Archiv [1], on the basis of an extrapolation from a naïve GIST cohort from Ticino, Switzerland [2], we proposed a possible 4 % prevalence of KRAS mutations in GISTs. A recent paper by Lasota et al. reported about the absence of KRAS mutations in a large cohort of GISTs (n =514) [3] which, to the best of our knowledge, constitutes by itself about 60 % of cases so far studied for this molecular alteration [4][5][6][7]. Thus, considering the cumulative evidence produced so far, the actual possible prevalence of KRAS mutations in GISTs seems much lower than the one we hypothesized, possibly approaching 0.3 %.

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“…1 Also, previous studies have failed to detect KRAS mutations in GISTs, although they were based on relatively small number of cases. [15][16][17][18] More recently, concurrent KRAS mutations were reported in KIT-or PDGFRA-mutant GISTs. 3 The study consisted of two GIST cohorts tested independently in Locarno, Switzerland and in Milan, Italy by standard PCR amplification and Sanger direct sequencing of PCR products.…”

Section: Discussionmentioning

confidence: 99%

No KRAS mutations found in gastrointestinal stromal tumors (GISTs): molecular genetic study of 514 cases

Lasota

Coates

et al. 2013

Modern Pathology

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. A great majority of GISTs is driven by pathological activation of KIT or platelet-derived growth factor receptor-α (PDGFRA), two closely related receptor tyrosine kinases. However, other genetic changes including gain-of-function BRAF mutations and loss of succinate dehydrogenase (SDH) complex activity have been identified in the subsets of KIT-, PDGFRA-wild type tumors. Genetic mutations affecting KIT, PDGFRA, BRAF and SDH complex functions are believed to be mutually exclusive events. Recently, KRAS codon 12 and 13 mutations were reported in a small subset of KIT or PDGFRA mutant GISTs. Moreover, in in vitro experiments, KIT mutants with concurrent KRAS mutation showed resistance to imatinib, a receptor tyrosine kinase inhibitor used in GIST treatment. The aim of this study was to evaluate a large cohort of GISTs to define frequency and clinical significance of KRAS mutations in this type of cancer. A well-characterized cohort of 514 GISTs was screened for KRAS mutations using Sanger sequencing (n=450) and pyrosequencing (n=64). In all, 350 gastric, 100 intestinal and 64 primary disseminated GISTs were analyzed. No KRAS mutations were found. In GIST, KRAS mutations are extremely rare if they exist (<0.2%). Thus, mutational activation of KRAS does not seem to play any significant role in the development and progression of this type of cancer.

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Molecular characterization of an Italian series of sporadic GISTs

Cited by 18 publications

References 20 publications

Mutational spectrum and classification of novel mutations in patients with metastatic gastrointestinal stromal tumours

Mutational spectrum and classification of novel mutations in patients with metastatic gastrointestinal stromal tumours

On the prevalence of KRAS mutations in GISTs

No KRAS mutations found in gastrointestinal stromal tumors (GISTs): molecular genetic study of 514 cases

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