Amplified and Homozygously Deleted Genes in Glioblastoma: Impact on Gene Expression Levels

Abstract

BackgroundGlioblastoma multiforme (GBM) displays multiple amplicons and homozygous deletions that involve relevant pathogenic genes and other genes whose role remains unknown.MethodologySingle-nucleotide polymorphism (SNP)-arrays were used to determine the frequency of recurrent amplicons and homozygous deletions in GBM (n = 46), and to evaluate the impact of copy number alterations (CNA) on mRNA levels of the genes involved.Principal FindingsRecurrent amplicons were detected for chromosomes 7 (50%), 12 (22%), 1 (11%), 4 (9%), 11 (4%), and 17 (4%), whereas homozygous deletions involved chromosomes 9p21 (52%) and 10q (22%). Most genes that displayed a high correlation between DNA CNA and mRNA levels were coded in the amplified chromosomes. For some amplicons the impact of DNA CNA on mRNA expression was restricted to a single gene (e.g., EGFR at 7p11.2), while for others it involved multiple genes (e.g., 11 and 5 genes at 12q14.1–q15 and 4q12, respectively). Despite homozygous del(9p21) and del(10q23.31) included multiple genes, association between these DNA CNA and RNA expression was restricted to the MTAP gene.ConclusionsOverall, our results showed a high frequency of amplicons and homozygous deletions in GBM with variable impact on the expression of the genes involved, and they contributed to the identification of other potentially relevant genes.

Elucidation of the genetic and epigenetic landscape alterations in RNA binding proteins in glioblastoma

“…At a 10% cut off, three genes METTL1, MRPS17 and CCT6A were found to be amplified while ELAVL2 was found to be deleted (Figure 4A). Interestingly, the segment containing METTL1 (12q14) has previously been reported to be amplified in GBM [17]. Further, we found that most of the amplified RBPs were present on chromosome 7, which is known to carry amplification of many genes (especially EGFR and MET) in GBM (Supplementary Table 4A) [18].…”

Expression of Methylthioadenosine Phosphorylase (MTAP) in Pilocytic Astrocytomas

“…We report that MTAP expression is retained in the majority of PAs. The few studies that have analyzed MTAP in gliomas reported MTAP deletions and reduced mRNA expression in pediatric [38] and adult glioblastomas [36,37,40,44] . We also observed reduced MTAP tumor expression in a small number of infiltrative diffuse astrocytomas (i.e.…”

“…in the lung, liver and breast [30,[33][34][35] . In tumors of the central nervous system, deletion and gene copy-number breakpoints of MTAP have been reported in glioblastomas [36,37] , and in pediatric high-grade gliomas [38] , respectively. However, none of these studies assessed MTAP expression by immunohistochemistry.…”

hMOB3 Modulates MST1 Apoptotic Signaling and Supports Tumor Growth in Glioblastoma Multiforme

“…1D); conversely, hMOB3B seems to be downregulated. The chromosome locus 9p21, on which the hMOB3B and IFNK genes are located, is frequently deleted (52%) or epigenetically inactivated in GBM (44,46,47), which might explain the varying mRNA levels of hMOB3B in our array and the publicly available Rembrandt and TCGA datasets. Importantly, we found that total hMOB3 protein levels were prominently upregulated in human GBM samples (Fig.…”