PDGFRA mutation

In vitro modeling demonstrated that EML4::NTRK3 confers imatinib resistance, while sensitizing GIST cells to NTRK inhibitors. This first reported instance of an NTRK fusion as a secondary event in GIST progression underscores the importance of testing for NTRK alterations in tumors that have developed resistance to tyrosine kinase inhibitors to ensure patients are offered all available therapeutic options.

P1/2, N=29, Completed, Blueprint Medicines Corporation | Active, not recruiting --> Completed

While imatinib revolutionized first-line therapy, resistance and specific mutation profiles necessitate subsequent generations of tyrosine kinase inhibitors (TKIs). Second- and third-generation TKIs have transformed the management of advanced GIST, extending survival and offering mutation-specific precision therapy. Ongoing research into resistance mechanisms, combination strategies, and novel inhibitors promises further optimization of patient-centered care.

Western blot and qRT-PCR tests validated these genes in GIST-T1 cells, and ssGSEA analysis indicated a significant relationship between these hub genes and immune cell infiltration. This study revealed a set of novel signature genes with high diagnostic value, offering promising targets for the diagnosis and treatment of GIST.

First-generation sequencing identified concurrent mutations in c-KIT exons 11 (V560D) and exon 17 (N822K), implicating these double mutations in acquired imatinib resistance. This case underscores the clinical significance of double mutations in GIST, the limitations of first-line therapy in such contexts, and the importance of early genetic profiling to inform personalized treatment strategies.

Their disease progression and prognosis are generally more favorable compared to adult-type high-grade gliomas. Molecular testing plays a crucial role in diagnosis and differential diagnosis, holding significant importance for treatment and prognosis evaluation.

Interestingly, the tumors exhibited different morphologies (epithelioid and spindle cell), distinct immunohistochemical profiles, and harbored different mutations (KIT and PDGFRA).ConclusionSporadic multiple gastrointestinal stromal tumors may have different morphological and immunohistochemical features, and they may also harbor two mutually exclusive mutations, such as KIT and PDGFRA. Recognition of this possibility is crucial for accurate diagnosis and the development of personalized therapy.

Mutations were 12 to 39 nucleotide deletion or duplication variants. Our results suggest that short read, amplicon-based NGS assays may miss a significant number of clinically actionable KIT mutations and that follow-up of KIT and PDGFRA NGS-negative cases by alternative testing modalities should be considered.

Our findings highlight the clinical relevance of integrating NGS into routine GIST management, particularly for the identification and interpretation of rare genetic variants. The study underscores the importance of data sharing and collective variant annotation to support accurate molecular classification, prognostic assessment, and therapeutic decision-making for individual patients.

INSM1 is highly expressed in human glioblastoma tumors and, during cortical development, in intermediate progenitor cells, which give rise to neurons. Remarkably, INSM1 knockdown in triple mutant NSCs and primary glioblastoma cells disrupts oncogenic gene expression and function and inhibits the in vivo tumorigenicity of triple mutant NSCs, highlighting the functional importance of an intermediate progenitor cell-like cell state in glioblastoma pathogenesis.

Using a 73-gene panel, we characterized the molecular characteristics of GISTs and revealed a correlation with their clinical features. Moreover, KIT/PDGFRA-dependent and KIT/PDGFRA-independent mechanisms underlying resistance to imatinib were explored. Overall, our 73-gene panel is sufficient for clinical application in cases of GISTs.

In addition, NGS identified MDM2 and MYC amplification. This is the first report describing an NF1-mutant GIST harboring coamplification of MDM2 and MYC and associated with a higher-grade tumor progression.