Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene

Indio, Valentina; Astolfi, Annalisa; Tarantino, Giuseppe; Urbini, Milena; Nannini, Margherita; Saponara, Maristella; Gatto, Lidia; Santini, Donatella; Valle, Ítalo Faria do; Castellani, Gastone; Remondini, Daniel; Fiorentino, Michelangelo; Mehren, Margaret von; Brandi, Giovanni; Biasco, Guido; Heinrich, Michael C.; Pantaleo, Maria A.

doi:10.3390/ijms19030732

Cited by 31 publications

(27 citation statements)

References 55 publications

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“…The D842V mutation is the most common mutation associated with primary resistance to imatinib because it alters the kinase domain formation and, therefore, negatively affects imatinib association [ 40 , 41 ]. In fact, the progression free survival (PFS) of patients treated with imatinib carrying the D842V mutation compared to non-D842Vs is statistically significant (2.8 vs. 28.5 months, respectively) [ 42 ].…”

Section: Immunotherapy In Gistsmentioning

confidence: 99%

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

Vallilas

Sarantis

Kyriazoglou

et al. 2021

IJMS

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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).

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Section: Immunotherapy In Gistsmentioning

confidence: 99%

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

Vallilas

Sarantis

Kyriazoglou

et al. 2021

IJMS

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“…After demultiplexing and adapter trimming, the paired-end reads were mapped with the pipeline TopHat2/Bowtie2 () on the human reference genome hg38 (). Single nucleotide variants and indels were called with SNVMix2 () and GATK HaplotypeCaller (), respectively, and chromosomal rearrangements were investigated with several computational tools including ChimeraScan, Defuse, TopHat-Fusion, FusionMap as previously described[3]. No specific mutations or molecular alterations of interest for a targeted therapy were found.…”

Section: Final Diagnosismentioning

confidence: 99%

Successful multidisciplinary clinical approach and molecular characterization by whole transcriptome sequencing of a cardiac myxofibrosarcoma: A case report

Saponara

Indio

Pizzi

et al. 2019

WJCC

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BACKGROUNDCardiac tumors are rare and complex entities. Surgery represents the cornerstone of therapy, while the role of adjuvant treatment remains unclear and, in case of relapse or metastatic disease, the prognosis is very poor. Lack of prospective, randomized clinical trials hinders the generation of high level evidence for the optimal diagnostic workup and multimodal treatment of cardiac sarcomas. Herein, we describe the multidisciplinary clinical management and molecular characterization of a rare case of cardiac myxofibrosarcoma in an elderly woman.CASE SUMMARYA 73-year-old woman presented signs and symptoms of acute left-sided heart failure. Imaging examination revealed a large, left atrial mass. With suspicion of a myxoma, she underwent surgery, and symptoms were promptly relieved. Histology showed a cardiac myxofibrosarcoma, a rare histotype of cardiac sarcoma. Eight months later, disease unfortunately relapsed, and after a multidisciplinary discussion, a chemotherapy with doxorubicin and then gemcitabine was started, achieving partial radiologic and complete metabolic response, which was maintained up to 2 years and is still present. This report is focused on the entire clinical path of our patient from diagnosis to follow-up, through surgery and strategies adopted at relapse. Moreover, due to their rarity, very little is known about the molecular landscape of myxofibrosarcomas. Thus, we also performed and described preliminary genome analysis of the tumor tissue to get further insight on mechanisms involved in tumor growth, and to possibly unveil new clinically actionable targets.CONCLUSIONWe report a case of cardiac myxofibrosarcoma that achieved a very good prognosis due to an integrated surgical, cardiac and oncologic treatment strategy.

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“…Crenolanib, a known a potent inhibitor of PDGFRA and PDGFRB, and avapritinib, a highly selective and potent KIT/PDGFRA inhibitor, have shown promising anti-proliferative activity against D842V mutant GIST ( 10 , 11 ). However, no actionable recurrent molecular events of clinical significance in D842V mutant GIST have been found, so the potential therapeutic scenario of this rare subset of GIST remains still limited ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profiling of PDGFRA Mutant GIST Reveals Immune Signatures as a Specific Fingerprint of D842V Exon 18 Mutation

et al. 2020

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Platelet Derived Growth Factor Receptor Alpha (PDGFRA) mutations occur in only about 5–7% of gastrointestinal stromal tumors (GIST), notably with alterations on exons 12/14/18. The most frequent PDGFRA mutation is the exon 18 D842V, which is correlated to specific clinico-pathological features, such as primary imatinib resistance and higher indolence. Here, we present a gene expression profile (GEP) comparison of D842V vs. PDGFRA with mutations other than D842V (non-D842V). GEP was followed by in silico bioinformatic analysis aimed at evaluating differential expression, tumor microenvironment composition and pathway enrichment. We found a large set of oncogenes, transcription factors and nuclear receptors downregulated in the D842V mutant. Conversely, D842V showed a significant enrichment of immune- and interferon- related gene signatures. Differences in tumor microenvironment composition were also highlighted, including a higher abundance of CD8+ T-cells and an overexpression of the T cell-inflamed signature in the D842V mutant subgroup, which is predictive of immunotherapy response. PDGFRA D842V vs. non-D842V GIST display a different expression profile, with a prominent immunological signature, that could represent a proof of principle for testing immunotherapeutic strategies in this drug-orphan subset of GIST.

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Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene

Cited by 31 publications

References 55 publications

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

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

Successful multidisciplinary clinical approach and molecular characterization by whole transcriptome sequencing of a cardiac myxofibrosarcoma: A case report

Gene Expression Profiling of PDGFRA Mutant GIST Reveals Immune Signatures as a Specific Fingerprint of D842V Exon 18 Mutation

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