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Updated: Jun 4, 2025
Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres
Published on: July 22, 2020
Novel structural variants that impact cell cycle genes are elucidated in metastatic gastrointestinal stromal tumors
Jesús Delgado-de la Mora1, Majd Al Assaad1, Stephanie Quitian2
1Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Ave, New York, NY 10065, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, 413 East 69th Street, New York, NY 10021, USA.
Abstract:
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the digestive tract. Despite multiple therapeutic advances, patients with advanced disease frequently develop resistance to tyrosine kinase inhibitors (TKIs), and therefore represent a therapeutic challenge. We employed whole genome sequencing (WGS) on three metastatic GISTs refractory to various TKIs and explored a publicly available cohort of 499 GISTs. This study sheds light on the clinical importance of alterations in cell cycle genes such as cyclin-dependent kinase 2 A (CDKN2A), and cyclin-dependent kinase 2B (CDKN2B), their frequent alteration in metastatic GISTs and their potential role in tumor progression of this neoplasm. Likewise, new structural variations were identified in cyclin-dependent kinase 12 (CDK12). Whole genome profiling of metastatic GIST provides new insights to advance precision care of the disease, focusing on new therapeutic possibilities, especially for emerging targets such as CDK12.
Insights
Advanced gastrointestinal stromal tumors (GISTs) often resist treatment. Whole genome sequencing revealed cell cycle gene alterations, like CDKN2A/B, and new CDK12 variations in resistant GISTs, offering new therapeutic targets.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract.
- Advanced GISTs frequently develop resistance to tyrosine kinase inhibitors (TKIs), posing a significant therapeutic challenge.
Purpose of the Study:
- To investigate genetic alterations in metastatic GISTs refractory to TKIs using whole genome sequencing (WGS).
- To identify potential new therapeutic targets and understand the role of cell cycle genes in GIST progression.
Main Methods:
- Whole genome sequencing (WGS) was performed on three metastatic GIST samples resistant to TKIs.
- Analysis of a public cohort of 499 GISTs was integrated to identify common genetic alterations.
Main Results:
- Frequent alterations in cell cycle genes, including cyclin-dependent kinase 2A (CDKN2A) and cyclin-dependent kinase 2B (CDKN2B), were observed in metastatic GISTs.
- Novel structural variations were identified in cyclin-dependent kinase 12 (CDK12).
Conclusions:
- Whole genome profiling of metastatic GISTs provides crucial insights into tumor progression and TKI resistance.
- Emerging targets like CDK12 present new therapeutic possibilities for advanced GIST patients, advancing precision oncology.
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