Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma

• Published in: Nature genetics Vol. 41; no. 4; pp. 465 - 472
• Main Authors: Gillespie, Yancey, Scherer, Stephen W, Gilbertson, Richard J, Ellison, David W, Lach, Boleslaw, Carlotti, Carlos G, Taylor, Michael D, Sunil Rao, J, Kongkham, Paul N, Dubuc, Adrian, Hamilton, Ronald L, Eberhart, Charles G, Rutka, James T, Nakahara, Yukiko, Boop, Frederick, Pollack, Ian F, Mack, Stephen, Northcott, Paul A, Croul, Sid, Ra, Young-Shin, Van Meter, Timothy, Mcleod, Jessica, Grundy, Richard, Feuk, Lars, Zilberberg, Karen, Bigner, Darrell, Peacock, John, Grajkowska, Wiesia, Wu, Xiaochong
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2009; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain; Brain cancer; Brain tumors; Cancer Research; Carcinogenesis; Cerebellar Neoplasms - enzymology; Cerebellar Neoplasms - genetics; Chromosomes; DNA damage; Fundamental and applied biological sciences. Psychology; Gene Amplification; Gene Deletion; Gene Function; Genes; Genes, Tumor Suppressor; Genetic aspects; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Histone-Lysine N-Methyltransferase - genetics; Histones - metabolism; Human Genetics; Humans; letter; Lysine - metabolism; Medical research; Medical sciences; Medulloblastoma; Medulloblastoma - enzymology; Medulloblastoma - genetics; Methylation; Neurology; Physiological aspects; Polymorphism, Single Nucleotide; Protein Processing, Post-Translational - genetics; Proteins; Risk factors; Sequence Deletion; Single nucleotide polymorphisms; Stem cells; Tumors of the nervous system. Phacomatoses; Canada; United States; Nervous system diseases; Regulation(control); Lysine; Medulloblastoma; Central nervous system disease; Genetics; Malignant tumor; Recurrent; Histone; Methylation; Cancer; Cerebral disorder
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.336

We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.