Monoallelic Expression Determines Oncogenic Progression and Outcome in Benign and Malignant Brain Tumors

Erin WALKER, Cindy Zhang, Pedro Castelo-Branco, Cynthia Hawkins, Wesley Wilson, Nataliya Zhukova, Noa Alon, Ana Novokmet, Berivan Baskin, Peter Ray, Christiane Knobbe, Peter Dirks, Michael Taylor, Sidney Croul, David Malkin, Uri Tabori

Research output: Contribution to journalArticle

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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
Original languageEnglish
Pages (from-to)636-644
Number of pages9
JournalCancer Research
Volume72
Issue number3
DOIs
Publication statusPublished - 2012
Externally publishedYes

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Brain Neoplasms
Neoplasms
Genes
Neoplasm Genes
Genome
Survival
Oligonucleotide Array Sequence Analysis
Oncogenes
Single Nucleotide Polymorphism
Carcinogenesis
Alleles
RNA
Pediatrics
Gene Expression

Cite this

WALKER, E., Zhang, C., Castelo-Branco, P., Hawkins, C., Wilson, W., Zhukova, N., ... Tabori, U. (2012). Monoallelic Expression Determines Oncogenic Progression and Outcome in Benign and Malignant Brain Tumors. Cancer Research, 72(3), 636-644. https://doi.org/10.1158/0008-5472.CAN-11-2266
WALKER, Erin ; Zhang, Cindy ; Castelo-Branco, Pedro ; Hawkins, Cynthia ; Wilson, Wesley ; Zhukova, Nataliya ; Alon, Noa ; Novokmet, Ana ; Baskin, Berivan ; Ray, Peter ; Knobbe, Christiane ; Dirks, Peter ; Taylor, Michael ; Croul, Sidney ; Malkin, David ; Tabori, Uri. / Monoallelic Expression Determines Oncogenic Progression and Outcome in Benign and Malignant Brain Tumors. In: Cancer Research. 2012 ; Vol. 72, No. 3. pp. 636-644.
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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",
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WALKER, E, Zhang, C, Castelo-Branco, P, Hawkins, C, Wilson, W, Zhukova, N, Alon, N, Novokmet, A, Baskin, B, Ray, P, Knobbe, C, Dirks, P, Taylor, M, Croul, S, Malkin, D & Tabori, U 2012, 'Monoallelic Expression Determines Oncogenic Progression and Outcome in Benign and Malignant Brain Tumors', Cancer Research, vol. 72, no. 3, pp. 636-644. https://doi.org/10.1158/0008-5472.CAN-11-2266

Monoallelic Expression Determines Oncogenic Progression and Outcome in Benign and Malignant Brain Tumors. / WALKER, Erin; Zhang, Cindy; Castelo-Branco, Pedro; Hawkins, Cynthia; Wilson, Wesley; Zhukova, Nataliya; Alon, Noa; Novokmet, Ana; Baskin, Berivan; Ray, Peter; Knobbe, Christiane; Dirks, Peter; Taylor, Michael; Croul, Sidney; Malkin, David; Tabori, Uri.

In: Cancer Research, Vol. 72, No. 3, 2012, p. 636-644.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Monoallelic Expression Determines Oncogenic Progression and Outcome in Benign and Malignant Brain Tumors

AU - WALKER, Erin

AU - Zhang, Cindy

AU - Castelo-Branco, Pedro

AU - Hawkins, Cynthia

AU - Wilson, Wesley

AU - Zhukova, Nataliya

AU - Alon, Noa

AU - Novokmet, Ana

AU - Baskin, Berivan

AU - Ray, Peter

AU - Knobbe, Christiane

AU - Dirks, Peter

AU - Taylor, Michael

AU - Croul, Sidney

AU - Malkin, David

AU - Tabori, Uri

PY - 2012

Y1 - 2012

N2 - 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

AB - 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

KW - Brain Tumor

KW - Monoallelic Expression

U2 - 10.1158/0008-5472.CAN-11-2266

DO - 10.1158/0008-5472.CAN-11-2266

M3 - Article

VL - 72

SP - 636

EP - 644

JO - Cancer research. Supplement

JF - Cancer research. Supplement

SN - 0008-5472

IS - 3

ER -