Frequent mutations in MLH1, MET, KIT, PDGFRA, and PIK3CA genes in human gastrointestinal stromal tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10544-10544 ◽  
Author(s):  
Zhi Xu ◽  
Xinying Huo ◽  
Chuanning Tang ◽  
Hua Ye ◽  
Feng Lou ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Human Cancer ◽  
New Drugs ◽  
Missense Mutations ◽  
Ion Torrent ◽  
Exon 2 ◽  
Sequencing Platform ◽  
Stromal Tumors ◽  
Frequent Mutations

10544 Background: Identifying mutations in individual tumor is critical to improve the efficacy of cancer therapy by matching targeted drugs to specific mutations. Gastrointestinal stromal tumor (GIST) is a stromal or mesenchymal subepithelial neoplasm affecting the gastrointestinal tract and it frequently contains an activating mutation in either the KIT or platelet-derived growth factor A (PDGFRA) gene. Although GIST is highly responsive to several selective tyrosine kinase inhibitors, combined use of inhibitors targeting other mutations is needed to further prolong survival. Methods: In this study, we aim to screen and identify genetic mutations in GIST for targeted therapy using the new Ion Torrent next-generation sequencing platform. Results: By utilizing the Ion Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes from DNA extracted from formalin-fixed and paraffin-embedded (FFPE) samples of 125 human gastrointestinal stromal tumors, set up stringent parameters for reliable variant calling by filtering out potential raw base calling errors, and identified frequent mutations in PDGFRA, KIT, APC, MLH1, MET, RET, and PIK3CA. Moreover, frequent missense mutations were detected in MLH1 (12%), MET (16.8%), KIT (51.2%), and PIK3CA (41.6%) genes. The mutations in MLH1 gene were frequently detected in the exon 14, while MET gene was frequently mutated in the exon 2. In addition, we identified missense mutations in other genes, including FLT3, KRAS, PDGFRA, and STK11, at lower frequencies. Conclusions: This study demonstrates the utility of using Ion Torrent sequencing to efficiently identify human cancer mutations. With the finding of the frequent mutations in MLH1 and MET genes, in addition to KIT, PDGFRA and PIK3CA, in GISTs, this study provides a molecular basis for clinically developing new drugs targeting these gene mutations for GIST therapy.

scholarly journals Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

2021 ◽  
Vol 22 (2) ◽  
pp. 493
Author(s):  
Christos Vallilas ◽  
Panagiotis Sarantis ◽  
Anastasios Kyriazoglou ◽  
Evangelos Koustas ◽  
Stamatios Theocharis ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Cancer Therapeutics ◽  
Gastrointestinal Neoplasms ◽  
Mesenchymal Tumors ◽  
Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

scholarly journals Prognostic value of Onodera’s nutritional index for intermediate- and high-risk gastrointestinal stromal tumors treated with or without tyrosine kinase inhibitors

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Feng Wang ◽  
Tingting Tao ◽  
Heng Yu ◽  
Yingying Xu ◽  
Zhi Yang ◽  
...  
Keyword(s):  
Propensity Score ◽  
Propensity Score Matching ◽  
Prognostic Marker ◽  
Gastrointestinal Stromal Tumors ◽  
Prognostic Value ◽  
Kinase Inhibitors ◽  
Rank Test ◽  
Stromal Tumors ◽  
Lymphocyte Ratio ◽  
Nutritional Index

Abstract Background Immunoinflammatory and nutritional markers, such as the peripheral blood neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and Onodera’s prognostic nutritional index (OPNI), have gained considerable attention and have been preliminarily revealed as prognostic markers of gastrointestinal stromal tumors (GISTs). Methods In this study, we first investigated the prognostic value of OPNI in GISTs treated with or without TKIs based on the propensity score matching (PSM) method. All of the patients had received surgical resection for primary GIST, and data from 2010 to 2018 were initially and retrospectively identified from our gastrointestinal center. Recurrence-free survival (RFS) was calculated by the Kaplan–Meier method and compared by the log-rank test. Results The patients were divided into groups treated and not treated with TKIs, and we used the propensity score matching method to homogenize their baseline data. Multivariate Cox proportional hazard regression models were applied to identify associations with outcome variables. A total of 563 GISTs were initially chosen, and 280 of them were included for analysis under the inclusion criteria. After PSM, there were 200 patients included. Multivariate analyses identified OPNI as an independent prognostic marker that was associated with primary site, tumor size, mitotic index, tumor rupture, necrosis, and modified NIH risk classification. Low OPNI (< 42.6; HR 0.409; P < 0.001) was associated with worse RFS. Conclusions Preoperative OPNI is a novel and useful prognostic marker for GISTs both treated and not treated with TKIs. Higher NLR and PLR have negative effects on RFS.

scholarly journals The importance of molecular biology in development, prognosis, treatment and resistance to targeted therapy in gastrointestinal stromal tumors

2011 ◽  
pp. 69-79
Author(s):  
Alessandro Comandone ◽  
Elisa Berno ◽  
Simona Chiadò Cutin ◽  
Antonella Boglione
Keyword(s):  
Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Neoplastic Transformation ◽  
Response To Therapy ◽  
Mesenchymal Tumors ◽  
Kit Mutation ◽  
Stromal Tumors ◽  
Receive Treatment

Gastrointestinal stromal tumors (GISTs) are the commonest mesenchymal tumors of the gastroenteric tract, and are generally believed to originate from the neoplastic transformation of the interstitial cells of Cajal, the pacemaker structures of the stomach and intestine. Exon and genetic mutations (point/deletions) are fundamental for the development of GISTs: the constitutional characteristic of this neoplasm is the presence of the cell surface Kit receptor. Kit is the product of the proto-oncogene cKit, situated in chromosome 4. Ninety-eight percent of GISTs express mutated isoforms of Kit or of PDGFRA (Platelet growth factor receptor a). Kit mutation is the basic condition for autophosphorylation of tyrosine kinase residues in proteins. Autophosphorylation initiates pathogenetic processes in Cajal cells, toward a neoplastic transformation. Imatinib mesilate and, more recently, sunitinib are tyrosine kinase inhibitors, specific antagonists for Kit and PDGFRA, with good activity against GISTs. Most molecular and clinical data currently available concern imatinib. Exon mutations are strategic as prognostic and as predictive factors. In recent years, much evidence suggests that survival, response to therapy and resistance to imatinib are related to different mutations. In the near future, GIST patients will receive treatment differentiated by expressed Kit and PDGFRA mutations, thus truly individualized therapy.

scholarly journals Mutation status and immunohistochemical correlation of EGFR mutations in gastrointestinal stromal tumors

2021 ◽  
Vol 24 (1) ◽  
pp. 67-72
Author(s):  
H Ozkayalar ◽  
MC Ergoren ◽  
G Tuncel ◽  
S Kurt ◽  
E Cevik ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Stromal Tumors ◽  
Molecular Alterations ◽  
Treatment Regimes ◽  
Research Areas ◽  
Turkish Patients

Abstract Being one of the leading causes of cancer deaths worldwide and their resistance to conventional treatment methods, made gastrointestinal stromal tumors (GISTs) one of the hot topics in medical research areas in the past decade. To investigate molecular alterations underlying the tumor is of great importance to be able to develop new, targeted treatment options. In this study, GIST samples obtained from 40 Turkish patients were analyzed for actionable epidermal growth factor receptor (EGFR) mutations that are related to treatment regimes in non small cell lung cancer (NSCLC) to understand whether EGFR expression is altered in GISTs. Established alterations in EGFR can make the use of tyrosine kinase inhibitors possible, which are currently used in cancer therapy, especially in NSCLC. Our results indicated that EGFR mutations are rare in GISTs. Further research is needed to sequence whole coding regions of the gene to investigate new actionable mutations in EGFR in an increased sample size.

A familial germline mutation in KIT associated with achalasia, mastocytosis and gastrointestinal stromal tumors shows response to kinase inhibitors

2019 ◽  
Vol 233-234 ◽  
pp. 1-6 ◽  
Author(s):  
Alison L. Halpern ◽  
Robert J. Torphy ◽  
Martin D. McCarter ◽  
Cosimo G. Sciotto ◽  
L. Michael Glode ◽  
...  
Keyword(s):  
Germline Mutation ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Stromal Tumors

Surgical Management of Advanced Gastrointestinal Stromal Tumors After Treatment With Targeted Systemic Therapy Using Kinase Inhibitors

2006 ◽  
Vol 24 (15) ◽  
pp. 2325-2331 ◽  
Author(s):  
Chandrajit P. Raut ◽  
Matthew Posner ◽  
Jayesh Desai ◽  
Jeffrey A. Morgan ◽  
Suzanne George ◽  
...  
Keyword(s):  
Overall Survival ◽  
Disease Progression ◽  
Stable Disease ◽  
Systemic Therapy ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Stromal Tumors ◽  
Surgical Result

PurposeWhile targeted inhibitors of tyrosine kinase activity demonstrate dramatic efficacy in the majority of patients with advanced gastrointestinal stromal tumors (GISTs), cure remains elusive and resistance to systemic therapy is a challenge. To assess the role of surgery in multimodality management of GISTs, we studied postoperative outcomes in patients treated with targeted kinase inhibitors for advanced GIST.MethodsWe evaluated outcomes in a single institution series of 69 consecutive patients who underwent surgery for advanced GISTs while receiving kinase inhibitors. Patients were categorized based on extent of disease before surgery (stable disease, limited disease progression, generalized disease progression) and surgical result (no evidence of disease, minimal residual disease, bulky residual disease).ResultsDisease status before surgery was associated with surgical result (P < .0001; median follow-up, 14.6 months). After surgery, there was no evidence of disease in 78%, 25%, and 7% of patients with stable disease, limited progression, and generalized progression, respectively. Bulky residual disease remained after surgery in 4%, 16%, and 43% of the patients with stable disease, limited progression, and generalized progression. Twelve-month progression-free survival was 80%, 33%, and 0% for patients with stable disease, limited progression, and generalized progression (P < .0001). Twelve-month overall survival was 95%, 86%, and 0% for patients with stable disease, limited progression, and generalized progression (P < .0001).ConclusionPatients with advanced GISTs exhibiting stable disease or limited progression on kinase inhibitor therapy have prolonged overall survival after debulking procedures. Surgery has little to offer in the setting of generalized progression.

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