Novel structural variants that impact cell cycle genes are elucidated in metastatic gastrointestinal stromal tumors.

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.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Max F. Levine reports a relationship with Isabl Inc. that includes: employment. Aditya Deshpande reports a relationship with Isabel Inc. that includes: employment. Juan S. Medina-Martinez reports a relationship with Isabl Inc that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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