High-resolution global genomic survey of 178 gliomas reveals novel regions of copy number alteration and allelic imbalances

Abstract

Primary brain tumors are the fourth leading cause of cancer mortality in adults under the age of 54 years and the leading cause of cancer mortality in children in the United States. Therapy for the most common type of primary brain tumors, gliomas, remains suboptimal. The development of new and more effective treatments will likely require a better understanding of the biology of these tumors. Here, we show that use of the high-density 100K single-nucleotide polymorphism arrays in a large number of primary tumor samples allows for a much higher resolution survey of the glioma genome than has been previously reported in any tumor type. We not only confirmed alterations in genomic areas previously reported to be affected in gliomas, but we also refined the location of those sites and uncovered multiple, previously unknown regions that are affected by copy number alterations (amplifications, homozygous and heterozygous deletions) as well as allelic imbalances (loss of heterozygosity/gene conversions). The wealth of genomic data produced may allow for the development of a more rational molecular classification of gliomas and serve as an important starting point in the search for new molecular therapeutic targets.

Figure 1

Representative diagrams of correlation between SNP copy numbers and mRNA expression for neighboring gene probe sets. A, CDKN2A (homozygous and heterozygous deletion). B, PTEN (heterozygous deletion). C, EGFR (amplified). D, XIST (gender specific). mRNA expression units are arbitrary.

Figure 2

Detailed histogram representation of heterozygous DNA (A) and homozygous (B) deletions as well as amplifications at the level of five copies or more (C) found segregated by histopathologic diagnosis. Y axis, ratio of samples showing the alteration at a given SNP. Numbers below each subpanel, chromosome number.

Figure 3

Top, histogram representing DNA amplifications found in all samples by analyzing copy number alterations. Different thresholding conditions are shown. X axis, all somatic chromosomes; the length of the segment is proportional to the size of chromosome. Y axis, ratio of samples showing a particular amplification. Bottom, heat map showing the altered SNP (amplified at three copies or more) as a green dot against the background. Numbers on top, chromosome numbers. Different types of tumors are noted to the right (Astro, astrocytoma; Oligo, oligodendroglioma) and separated by straight line.

Figure 4

Detailed histogram representing LOH with a pLOH > 10 segregated by histopathologic diagnosis. Y axis, ratio of samples showing the alteration at a given SNP. Numbers below, chromosome number.

Figure 5

A, correlation heat map showing the altered SNP as calculated by LOH analysis (green) or deletions by copy number alteration (blue). Numbers below, chromosome numbers. Shown here are only the glioblastoma samples. B, heat map showing the alterations found in mixed tumors: amplified SNPs (red) and deletions/LOH (green). Numbers on top, chromosome numbers. For comparison purposes, two panels showing the consensus alterations (defined as changes seen in more than five samples) in all glioblastomas and oligodendrogliomas are shown on top of the main panel. The alterations found on oligodendrogliomas and GBMs that are mirrored in mixed tumors are highlighted by an ellipsoidal or rectangular marquee, respectively.