Cytogenetic and molecular analyses of 291 gastrointestinal stromal tumors: site-specific cytogenetic evolution as evidence of pathogenetic heterogeneity

Abstract

Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm with variable behavior. An increased understanding of the tumor pathogenesis may improve clinical decision-making. Our aim was to obtain more data about the overall chromosome aberrations and intratumor cytogenetic heterogeneity in GIST. We analyzed 306 GIST samples from 291 patients using G-banding, direct sequencing, and statistics. Clonal chromosome aberrations were found in 81% of samples, with 34% of 226 primary tumors demonstrating extensive cytogenetic heterogeneity. 135 tumors had simple (≤5 changes) and 91 had complex (>5 changes) karyotypes. The karyotypically complex tumors more often were non-gastric ( P < 0.001), larger ( P < 0.001), more mitotically active ( P = 0.009) and had a higher risk of rupture ( P < 0.001) and recurrence ( P < 0.001). Significant differences between gastric and non-gastric tumors were found also in the frequency of main chromosome losses: of 14q (79% vs. 63%), 22q (38% vs. 67%), 1p (23% vs. 88%), and 15q (18% vs. 77%). Gastric PDGFRA -mutated tumors, compared with gastric KIT -mutated, had a lower incidence of 22q losses (18% vs. 43%) but a higher rate of 1p losses (42% vs. 22%). The present, largest by far karyotypic study of GISTs provides further evidence for the existence of variable pathogenetic pathways operating in these tumors’ development.

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

“…Most metastasizing high‐risk GISTs showed complex CIN profiles, while the less aggressive, non‐metastatic tumours showed a simpler CIN pattern. Loss of chromosome 14 is the earliest and most frequent aberration in GIST, followed by loss of additional chromosomes in higher‐risk tumours [ 55 , 56 , 57 ]. Based on the pattern of CNVs, the groups in our cohort seem to represent different stages of the genomic evolution of GIST, as the simplest samples contain only a deletion of one copy of chromosome 14, in addition to a KIT or PDGFRA mutation.…”

The spectrum and significance of secondary (co‐occurring) genetic alterations in sarcomas: the hallmarks of sarcomagenesis

“…Some studies suggest these changes might be site‐dependent (gastric versus nongastric) and that these chromosomal changes might be early events in tumorigenesis [126]. Increased karyotypic complexity in GISTs has been shown to correlate with recurrence risk and nongastric location [127]. Recurrent copy number gains involving 1q, 12q, and 13q [128] and losses involving 1p ( RUNX3 , ARID1A ), 13q14.2 ( MIR15A, MIR16‐1 ), 11q22‐24 (e.g.…”