Comparable Genomic Copy Number Aberrations Differ across Astrocytoma Malignancy Grades

Abstract

A collection of intracranial astrocytomas of different malignancy grades was analyzed for copy number aberrations (CNA) in order to identify regions that are driving cancer pathogenesis. Astrocytomas were analyzed by Array Comparative Genomic Hybridization (aCGH) and bioinformatics utilizing a Bioconductor package, Genomic Identification of Significant Targets in Cancer (GISTIC) 2.0.23 and DAVID software. Altogether, 1438 CNA were found of which losses prevailed. On our total sample, significant deletions affected 14 chromosomal regions, out of which deletions at 17p13.2, 9p21.3, 13q12.11, 22q12.3 remained significant even at 0.05 q-value. When divided into malignancy groups, the regions identified as significantly deleted in high grades were: 9p21.3; 17p13.2; 10q24.2; 14q21.3; 1p36.11 and 13q12.11, while amplified were: 3q28; 12q13.3 and 21q22.3. Low grades comprised significant deletions at 3p14.3; 11p15.4; 15q15.1; 16q22.1; 20q11.22 and 22q12.3 indicating their involvement in early stages of tumorigenesis. Significantly enriched pathways were: PI3K-Akt, Cytokine-cytokine receptor, the nucleotide-binding oligomerization domain (NOD)⁻like receptor, Jak-STAT, retinoic acid-inducible gene (RIG)-I-like receptor and Toll-like receptor pathways. HPV and herpex simplex infection and inflammation pathways were also represented. The present study brings new data to astrocytoma research amplifying the wide spectrum of changes that could help us identify the regions critical for tumorigenesis.

Keywords: GISTIC2.0.23; aCGH; astrocytoma; comparative genomic hybridization; copy number aberrations.

Figure 1

Frequent aberrant regions shared among the highest number of investigated patients.

Figure 2

Heat map images of four different intracranial astrocytic brain tumor sample pools based on total segmented DNA copy number variation profiles. Images were analysed using GISTIC (v2.0.23). In each heat map, the samples are arranged from left to right, and chromosome arrangement flows vertical, top to bottom ordering. Red represents CN gain and blue represents CN loss. (A) all samples; (B) malignant samples; (C) high grade samples; (D) low grade samples.

Figure 3

Matrix layout for all 65 genes across 35 functional categories (association calculated by DAVID), sorted by size. Dark circles in the matrix indicate functional categories with genes that are part of the intersecting groups, that is, are associated with each category of the set. The bar plot above the matrix depicts the number of shared genes, while the horizontal bar plot on the left reflects the number of genes within each group. Blue and red colored bars indicate the respective aberration.

Figure 4

Enrichment analysis utilizing the KEGG pathway database. Analysis included genes from all malignant samples associated with both deleted and amplified regions. No significant enrichment was associated with amplified segments.