Genomic aberrations in cell cycle genes predict progression of -mutant gastrointestinal stromal tumors (GISTs).

Background: Activating mutations of the receptor tyrosine kinase are early events in the development of most gastrointestinal stromal tumors (GISTs). Although GISTs generally remain dependent on oncogenic during tumor progression, mutations alone are insufficient to induce malignant behavior. This is evidenced by -mutant micro-GISTs, which are present in up to one-third of normal individuals, but virtually never progress to malignancy.

Methods: We performed whole exome sequencing on 29 tumors obtained from 21 patients with high grade or metastatic -mutant GIST (discovery set). We further validated the frequency and potential prognostic significance of aberrations in and in an independent series of 71 patients with primary GIST (validation set).

Results: Using whole exome sequencing we found significant enrichment of genomic aberrations in cell cycle-associated genes (Fisher's Exact p = 0.001), most commonly affecting in our discovery set. We found a low mutational tumor burden in these 29 advanced GIST samples, a finding with significant implications for the development of immunotherapy for GIST. In addition, we found mutation of spliceosome genes in a minority of cases, implicating dysregulation of splicing as a potential cancer promoting mechanism in GIST. We next assessed the prognostic significance of or mutation/copy loss in an independent cohort of 71 patients with primary GIST. Genetic events (mutation, deletion, and/or LOH) involving at least one of the three genes examined were found in 17% of the very low-risk, 36% of the low-risk, 42% of the intermediate risk, 67% of the high-risk/low mitotic-count, and in 86% of the high-risk/high mitotic-count group. The presence of cell cycle-related events was associated with a significantly shorter relapse-free survival (median 67 months versus not reached;  < 0.0001) and overall survival (Log Rank, = 0.042).

Conclusion: Our results demonstrate that genomic events targeting cell cycle-related genes are associated with GIST progression to malignant disease. Based on this data, we propose a model for molecular pathogenesis of malignant GIST.