Copy-neutral loss of heterozygosity and chromosome gains and losses are frequent in gastrointestinal stromal tumors

Abstract

BackgroundA KIT gain of function mutation is present in 70% of gastrointestinal stromal tumors (GISTs) and the wild-type (WT) allele is deleted in 5 to 15% of these cases. The WT KIT is probably deleted during GIST progression. We aimed to identify the mechanism of WT KIT loss and to determine whether other genes are involved or affected.MethodsWhole-genome SNP array analyses were performed in 22 GISTs with KIT exon 11 mutations, including 11 with WT loss, to investigate the mechanisms of WT allele deletion. CGH arrays and FISH were performed in some cases. Common genetic events were identified by SNP data analysis. The 9p21.3 locus was studied by multiplex quantification of genomic DNA.ResultsChromosome instability involving the whole chromosome/chromosome arm (whole C/CA) was detected in 21/22 cases. The GISTs segregated in two groups based on their chromosome number: polyGISTs had numerous whole C/CA gains (mean 23, range [9 to 43]/3.11 [1 to 5]), whereas biGISTs had fewer aberrations. Whole C/CA losses were also frequent and found in both groups. There were numerous copy-neutral losses of heterozygosity (cnLOH) of whole C/CA in both polyGIST (7/9) and biGIST (9/13) groups. cnLOH were frequent on 4q, 11p, 11q, 1p, 2q, 3p and 10, and never involved 12p, 12q, 20p, 20q or 19q. Other genetic alterations included segmental chromosome abnormalities, complete bi-allelic deletions (homozygous deletions) and, more rarely, amplifications. Nine of 11 GISTs with homozygous KIT exon 11 mutations had cnLOH of chromosome 4.ConclusionThe cnLOH of whole C/CA is a frequent genetic alteration in GISTs and is closely associated with homozygous mutations of KIT and WT allele deletion.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-246) contains supplementary material, which is available to authorized users.

Massive interstitial copy-neutral loss-of-heterozygosity as evidence for cancer being a disease of the DNA-damage response

“…The vastly unequal rates of LOH and GOH occurrences also rendered unlikely that the massive numbers of LOHs arose from technical errors, which would have produced LOHs and GOHs randomly at comparable rates. In fact, based on the use of high density whole genome SNP arrays, occurrence of copy number-neutral LOHs was also found to be frequent in gastrointestinal stromal tumors where contamination of tumor samples with normal cells was generally low, leading to the suggestion that the frequency of copy number-neutral LOHs might tend to be underestimated in solid tumors on account of the low percentages of tumor cells in the samples [ 4 ]. In the present study, as indicated in Methods, all MM or mm genotypes arising from Mm genotypes must be 100 % for them to be called as LOHs in order to minimize or obviate the effects of varied percentages of tumor cells in a tumor sample.…”

“…As a common feature of cancer cells, LOHs have been investigated by cytogenetics, fluorescence in situ hybridization, comparative genomic hybridization (CGH), array-CGH, and single nucleotide polymorphism (SNP)-based microarrays [ 1 – 4 ]. With the application of next-generation sequencing, analysis of LOH in cancer can further be conducted at the level of single base resolution [ 5 , 6 ].…”

Circulating tumor DNA (ctDNA) in the era of personalized cancer therapy

“…The most usual mesenchymal tumors of the gastrointestinal tract are gastrointestinal stromal tumors (GISTs) [116,117]. GISTs are described by mutations in a receptor tyrosine family (mainly KIT gene) which are linked to the mast cell growth factor receptor or in the platelet-derived growth factor receptor alpha(PDGFRA) coding gene [118][119][120][121]. The relationship between tumor genotype and positive effect of adjuvant imatinib stated that GIST with a KIT exon 11-deletion beneficially respond to treatment, with a considerably extended progression free survival (PFS) compared with placebo [122][123][124].…”

Pan cancer patterns of allelic imbalance from chromosomal aberrations in 33 tumor types

“…Recent pan-cancer investigations have identified evidence of focal LOH events accompanying mutations in genes involved in DNA damage repair pathways (Knijnenburg et al 2018), as well as those accompanying polymorphisms in essential genes that result in cancer cell-specific vulnerabilities (Nichols et al). However, very few studies have described the vital role of large, chromosome-arm level cnLOH in the development of hematologic malignancies (O'Keefe et al 2010;Stirewalt et al 2014;Schwartz and Papenhausen 2017), gastrointestinal tumors (Lourenço et al 2014) and colorectal cancer (Melcher et al 2011). Therefore, it is crucial to understand and identify the landscape of these cnLOH events across tumor sites to better understand their role in the complex mechanisms of tumorigenesis such as those contributing to the multi-hit pathogenesis of tumors.…”