Journal Article

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

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

2010

Overview

Germline mutations in PARK2 are a well-known cause of the neurodegenerative disorder Parkinson's disease. Here, Timothy Chan and colleagues report somatic mutations and intragenic deletions of PARK2 in glioblastoma, colon cancer and lung cancer. Mutation of the gene PARK2 , which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease 1 , 2 , 3 . 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Agriculture / Animal Genetics and Genomics / Animals / Base Sequence / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Blotting, Western / Brain / Cancer / Cancer Research / Cell Line, Tumor / Charitable foundations / Colonic Neoplasms - genetics / Comparative Genomic Hybridization / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / DNA Mutational Analysis / Fundamental and applied biological sciences. Psychology / Gene Dosage / Gene expression / Gene Function / Gene mutations / Genetic aspects / Genetic Variation / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Genomics / Genotype / Glioblastoma - genetics / Glioblastoma - pathology / Glioblastoma multiforme / Health aspects / Human Genetics / Humans / letter / Lung Neoplasms - genetics / Medical sciences / Mice / Mice, SCID / Models, Molecular / Mutation / Neoplasms, Experimental - genetics / Neoplasms, Experimental - pathology / Neurology / Parkinson Disease - genetics / Parkinson's disease / Physiological aspects / Prevention / Protein Structure, Tertiary / Risk factors / Transplantation, Heterologous / Tumors of the nervous system. Phacomatoses / Ubiquitin / Ubiquitin-Protein Ligases - chemistry / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Ubiquitination