Abstract
Although monoallelic expression (MAE) is a frequent genomic event in normal tissues, its role in tumorigenesis remains unclear. Here we carried out single-nucleotide polymorphism arrays on DNA and RNA from a large cohort of pediatric and adult brain tumor tissues to determine the genome-wide rate of MAE, its role in specific cancer-related genes, and the clinical consequences of MAE in brain tumors. We also used targeted genotyping to examine the role of tumor-related genes in brain tumor development and specifically examined the clinical consequences of MAE at TP53 and IDH1. The genome-wide rate of tumor MAE was higher than in previously described normal tissue and increased with specific tumor grade. Oncogenes, but not tumor suppressors, exhibited significantly higher MAE in high-grade compared with low-grade tumors. This method identified nine novel genes highly associated with MAE. Within cancer-related genes, MAE was gene specific; hTERT was most significantly affected, with a higher frequency of MAE in adult and advanced tumors. Clinically, MAE at TP53 exists only in mutated tumors and increases with tumor aggressiveness. MAE toward the normal allele at IDH1 conferred worse survival even in IDH1 mutated tumors. Taken together, our findings suggest that MAE is tumor and gene specific, frequent in brain tumor subtypes, and may be associated with tumor progression/aggressiveness. Further exploration of MAE at relevant genes may contribute to better understanding of tumor development and determine survival in brain tumor patients.
Highlights
LOH of cancer-associated genes is a common and important mechanism in carcinogenesis
Genomic rate of monoallelic expression (MAE) in brain tumors To assess the magnitude of MAE in brain tumors in an unbiased manner and to uncover genes that use MAE and contribute to tumorigenesis, we carried out a genome-wide analysis of MAE using Affymetrix single-nucleotide polymorphism (SNP) 6.0 arrays in a series of 51 low- and high-grade brain tumors (Table 1)
To detect MAE, we only considered SNPs for which the DNA genotype was heterozygous, and we removed all homozygous DNA genotypes prior to any analysis
Summary
LOH of cancer-associated genes is a common and important mechanism in carcinogenesis. LOH at the level of the RNA, or monoallelic gene expression (MAE), is a much less understood phenomenon. MAE is defined as expression of a gene that is restricted to one allele in the presence of a diploid, heterozygous genome and is observed for imprinted genes and random X inactivation (lyonization). MAE has been observed in the odorant receptor, immune receptor, and immunoglobulin classes of genes [1, 2]. Expression is typically expected to occur from both parental alleles without preference. Recent studies have uncovered a potential role for random MAE, as well as differential allele-specific expression
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