Chromosomal instability and a deregulated cell cycle are intrinsic features of high‐risk gastrointestinal stromal tumours with a metastatic potential

Abstract

Patients with localized, high‐risk gastrointestinal stromal tumours (GIST) benefit from adjuvant imatinib treatment. Still, approximately 40% of patients relapse within three years after adjuvant therapy and the clinical and histopathological features currently used for risk classification cannot precisely predict poor outcomes after standard treatment. This study aimed to identify genomic and transcriptomic profiles that could be associated with disease relapse and thus a more aggressive phenotype. Using a multi‐omics approach, we analysed a cohort of primary tumours from patients with untreated, resectable high‐risk GISTs. We compared patients who developed metastatic disease within three years after finishing adjuvant imatinib treatment and patients without disease relapse after more than five years of follow‐up. Combining genomics and transcriptomics data, we identified somatic mutations and deregulated mRNA (messenger RNA) and miRNA (micro RNA) genes intrinsic to each group. Our study shows that increased chromosomal instability, including chromothripsis and deregulated kinetochore and cell cycle signalling, separates high‐risk samples according to metastatic potential. The increased chromosomal instability seems to be an intrinsic feature for tumours that metastasise and should be further validated as a novel prognostic biomarker for high‐risk GIST.

Multi-omics reveals AKR1B1-regulated galactose metabolic as a driver of gastrointestinal stromal tumor progression

“…To obtain further insight into the GIST epigenome, Niinuma, T. et al [7] integrated the epigenomic and transcriptional data of GIST-T1 cells treated with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor, and identified hypermethylation of MEG3 is a frequent event and an indicator of poorer prognosis in GIST patients. Namløs, H. M. et al [8] integrated the genomic and transcriptomic analyses of untreated, resectable high-risk GISTs and showed increased chromosomal instability (CIN) is an intrinsic feature for tumors that metastasize. A quantitative proteomics analysis of GISTs demonstrated the importance of proteome characterization in promoting the understanding of the etiology of GIST progression [9].…”