Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

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Mazor, Tali ^[1] ; Chesnelong, Charles ^{[2, 3]} ; Pankov, Aleksandr ^[1] ; Jalbert, Llewellyn E. ^[4] ; Hong, Chibo ^[1] ; Hayes, Josie ^[1] ; Smirnov, Ivan V. ^[1] ; Marshall, Roxanne ^[5] ; Souza, Camila F. ^{[6, 7]} ; Shen, Yaoqing ^[8] ; Viswanath, Pavithra ^[4] ; Noushmehr, Houtan ^{[6, 7]} ; Ronen, Sabrina M. ^[4] ; Jones, Steven J. M. ^{[8, 9]} ; Marra, Marco A. ^{[8, 9]} ; Cairncross, J. Gregory ^[3] ; Perry, Arie ^{[1, 5]} ; Nelson, Sarah J. ^{[4, 10]} ; Chang, Susan M. ^[1] ; Bollen, Andrew W. ^[5] ; Molinaro, Annette M. ^{[11, 1]} ; Bengtsson, Henrik ^{[11, 12]} ; Olshen, Adam B. ^{[11, 12]} ; Weiss, Samuel ^{[2, 3]} ; Phillips, Joanna J. ^{[1, 5]} ; Luchman, H. Artee ^{[2, 3]} ; Costello, Joseph F. ^[1]

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^[1] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94158 - USA

^[2] Univ Calgary, Cumming Sch Med, Dept Cell Biol & Anat, Hotchkiss Brain Inst, Calgary, AB T2N 4N1 - Canada

^[3] Univ Calgary, Cumming Sch Med, Dept Clin Neurosci, Clark H Smith Brain Tumor Ctr, Arnie Charbonneau C, Calgary, AB T2N 4N1 - Canada

^[4] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94158 - USA

^[5] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94158 - USA

^[6] Univ Sao Paulo, Dept Genet, BR-14049900 Ribeirao Preto, SP - Brazil

^[7] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI 48202 - USA

^[8] British Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6 - Canada

^[9] Univ British Columbia, Dept Med Genet, Vancouver, BC V5Z 4S6 - Canada

^[10] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 - USA

^[11] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94158 - USA

^[12] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 - USA

• Tipo de documento: Artigo Científico
• Fonte: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 114, n. 40, p. 10743-10748, OCT 3 2017.
• Citações Web of Science: 33

Resumo

IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite D-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions. (AU)

• Processo FAPESP: 16/15485-8 - Biomarcadores clínicos em tumores do sistema nervoso central
• Beneficiário: Camila Ferreira de Souza
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 14/08321-3 - Identificação e caracterização de elementos genômicos funcionais associados com a progressão de gliomas de baixo grau a gliomas de alto grau: estudo integrado do genoma e epigenoma
• Beneficiário: Camila Ferreira de Souza
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/07925-5 - Softwares de código aberto contendo ferramentas estatísticas para análise e integração de conjuntos de dados epigenômicos produzidos em alta escala, a fim de decifrar e entender redes reguladoras de câncer
• Beneficiário: Houtan Noushmehr
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores