Single Nuclei-Derived Molecular Subtypes of Gastrointestinal Stromal Tumors Correlate with Clinicopathologic Features and Predict Clinical Outcomes

Historically, gastrointestinal stromal tumor (GIST) has been subtyped by oncogenic driver mutations. However, tumors with the same mutational profile can have variable biology. To further explore the impact of molecular diversity on GIST biology, we performed single nucleus RNA sequencing on 16 primary GIST and utilized an integrated single cell atlas of the normal GI tract composed from multiple publicly available datasets to identify six distinct GISTcell states. We then statistically estimated the relative abundances of these profiles in bulk transcriptomic data. These were used to define six common GISTmolecular subtypesbased upon one or two predominant tumorcell states. We found that thesemolecular subtypescorrelate with tumor locations, mutational profiles, and patient outcomes, and validated these subtypes in an independent international cohort. Thesemolecular subtypeshave the potential to be used for clinical prognostication for patients with GIST, identifying new therapeutic targets, and studying the cell of transformation of GIST.