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Veeriah, S. et al. Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nature Genet. 42, 77-82

Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Nature Genetics (Impact Factor: 29.65). 11/2009; 42(1):77-82. DOI: 10.1038/ng.491
Source: PubMed

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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    • "X-axis represent the size of the aberrations in Mb, y-axis represents the frequency in the data sets. Grey bars under the plots indicate the size range of somatic focal CNAs and CNVs. in the vicinity of common fragile sites (CFS) genes such as FHIT, WWOX and PARK2 [32] [52]. CNAs serve as important predictive and/or prognostic biomarkers in the clinic. "
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    • "Mutations in PARK2 gene are responsible for the development of a form of autosomal recessive juvenile Parkinsonism (AR-JP) characterized by all the classical symptoms of Parkinson disease (PD), such as tremor, rigidity and bradykinesia [2]. In addition to AR-JP, PARK2 has been recently linked to cancer [3] [4], leprosy [5], autism [6], type 2 diabetes mellitus [7] and Alzheimer's disease [8]. PARK2 gene spans more than 1.38 Mb of genomic DNA in the long arm of chromosome 6 (6q25.2-q27) "
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    • "by these selected events provides insights into signaling pathways that may drive the clinical behavior of individual tumors. For example previous reports have identified somatic mutations of NUMB in breast carcinoma and of PARK2 in GBM, colon, and lung cancers (Colaluca et al., 2008; Veeriah et al., 2010). We have identified homozygous deletions in both of these genes providing evidence that their tumor suppressor function extends to PDA. "
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