High density DNA array analysis reveals distinct genomic profiles in a subset of gastrointestinal stromal tumors

Abstract

Gastrointestinal stromal tumors (GISTs) generally harbor activating mutations in KIT or PDGFRA. Mutations in these receptor tyrosine kinases lead to dysregulation of downstream signaling pathways that contribute to GIST pathogenesis. GISTs with KIT or PDGFRA mutations also undergo secondary cytogenetic alterations that may indicate the involvement of additional genes important in tumor progression. Approximately 10-15% of adult and 85% of pediatric GISTs do not have mutations in KIT or in PDGFRA. Most mutant adult GISTs display large-scale genomic alterations, but little is know about the mutation-negative tumors. Using genome-wide DNA arrays, we investigated genomic imbalances in a set of 31 GISTs, including 10 KIT/ PDGFRA mutation-negative tumors from 9 adults and 1 pediatric case and 21 mutant tumors. While all 21 mutant GISTs exhibited multiple copy number aberrations, notably losses, 8 of the 10 KIT/PDGFRA mutation-negative GISTs exhibited few or no genomic alterations. One KIT/ PDGFRA mutation-negative tumor exhibiting numerous genomic changes was found to harbor an alternate activating mutation, in the serine-threonine kinase BRAF. The only other mutationnegative GIST with significant chromosomal imbalances was a recurrent metastatic tumor found to harbor a homozygous deletion in chromosome 9p. Similar findings in several KIT-mutant GISTs identified a minimal overlapping region of deletion of ~0.28 Mbp in 9p21.3 that includes only the CDKN2A/2B genes, which encode inhibitors of cell-cycle kinases. These results suggest that GISTs without activating kinase mutations, whether pediatric or adult, generally exhibit a much lower level of cytogenetic progression than that observed in mutant GISTs.

A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number

“…Wozniak et al 10 reported that the genomic profile of GISTs bearing PDGFRA and KIT mutations seems to be independent from the tumor mutational status. Consistent with our results, Belinsky et al 28 reported that most WT GISTs show few or no genomic alterations. Taken together, this suggests that adult WT GISTs show a minimal cytogenetic progression in comparison with mutant GISTs.…”

Mitotic Checkpoints and Chromosome Instability Are Strong Predictors of Clinical Outcome in Gastrointestinal Stromal Tumors

“…Previous copy number studies identified few aberrations in GISTs, deletions being more common than gains (6,(10)(11)(12)(37)(38)(39). The authors concluded that chromosome 14, 22, and 1p deletions were the most frequent aberrations.…”

“…Previous studies on GISTs have linked 9p21 alterations to tumor progression (11)(12)(13)(14)(15)(16)45), but the driver gene was not positively identified (CDKN2A, CDKN2B, or MTAP; refs. 37,39,[46][47][48]. Here, we have shown that homozygous deletions target CDKN2A and more specifically p16 INK4a .…”

Gastrointestinal stromal tumors

“…Less frequently observed are losses on chromosomes 1p, 9q, 11p, 17q, and gains on chromosomes 8q and 17q, which are also associated with malignant behavior [56,57,[59][60][61]. GISTs without mutations in KIT, PDGFRA or BRAF, whether pediatric or adult, have been shown to exhibit a much lower level of cytogenetic progression than observed in mutant GISTs [10,62] underscoring that mechanisms leading to tumor progression are different in mutant and wild-type GISTs.…”