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Somatic mutations of the Parkinson's disease–associated gene PARK2 in glioblastoma and other human malignancies

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Veeriah, Selvaraju, Taylor, Barry S, Meng, Shasha, Fang, Fang, Yilmaz, Emrullah, Vivanco, Igor, Janakiraman, Manickam, Schultz, Nikolaus, Hanrahan, Aphrothiti J, Pao, William, Ladanyi, Marc, Sander, Chris, Heguy, Adriana, Holland, Eric C, Paty, Philip B, Mischel, Paul S, Liau, Linda, Cloughesy, Timothy F, Mellinghoff, Ingo K, Solit, David B, Chan, Timothy A·2010·Nature Genetics

DOI 10.1038/ng.491

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Abstract

Mutation of the gene PARK2, which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease. In a search for multisite tumor suppressors, we identified PARK2 as a frequently targeted gene on chromosome 6q25.2–q27 in cancer. Here we describe inactivating somatic mutations and frequent intragenic deletions of PARK2 in human malignancies. The PARK2 mutations in cancer occur in the same domains, and sometimes at the same residues, as the germline mutations causing familial Parkinson's disease. Cancer-specific mutations abrogate the growth-suppressive effects of the PARK2 protein. PARK2 mutations in cancer decrease PARK2's E3 ligase activity, compromising its ability to ubiquitinate cyclin E and resulting in mitotic instability. These data strongly point to PARK2 as a tumor suppressor on 6q25.2–q27. Thus, PARK2, a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells.

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Authors: Veeriah, S., Taylor, B. S., Meng, S., Fang, F., Yilmaz, E., Vivanco, I., Janakiraman, M., Schultz, N., Hanrahan, A. J., Pao, W., Ladanyi, M., Sander, C., Heguy, A., Holland, E. C., Paty, P. B., Mischel, P. S., Liau, L., Cloughesy, T. F., Mellinghoff, I. K., Solit, D. B., & Chan, T. A.
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2009-11-29
Volume: 42
Issue: 1
Pages: 77-82
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/ng.491
OpenAlex: W2035799305
Cited by: 406
References: 58
FWCI: 9.85
Type: journal article
Language: en
Open access: green

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Somatic mutations of the Parkinson's disease–associated gene PARK2 in glioblastoma and other human malignancies

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