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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Available from: Nikolaus Schultz, Aug 27, 2015
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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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    ABSTRACT: The extent of focal chromosomal copy number aberrations (CNAs) in cancer has been uncovered through technical innovations and this discovery has been critical for the identification of new cancer driver genes in genomics projects such as TCGA and ICGC. Unlike constitutive copy number variations (CNVs), focal CNAs are the result of many selection events during the evolution of cancer genomes. Therefore it is possible that a single gene in a focal CNA gives the tumor a selective growth advantage. This concept has been instrumental in the discovery of new cancer driver genes. However, focal CNAs lack a consensus definition, therefore we propose one based on pragmatic considerations. We also describe different strategies to identify focal CNAs and procedures to distinguish them from large CNAs and CNVs.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 08/2014; 1843(11). DOI:10.1016/j.bbamcr.2014.08.001 · 5.30 Impact Factor
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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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    ABSTRACT: The completion of the Human Genome Project aroused renewed interest in alternative splicing, an efficient and widespread mechanism that generates multiple protein isoforms from individual genes. Although our knowledge about alternative splicing is growing exponentially, its real impact on cellular life is still to be clarified. Connecting all splicing features (genes, splice transcripts, isoforms, and relative functions) may be useful to resolve this tangle. Herein, we will start from the case of a single gene, Parkinson protein 2, E3 ubiquitin protein ligase (PARK2), one of the largest in our genome. This gene is implicated in the pathogenesis of autosomal recessive juvenile Parkinsonism and it has been recently linked to cancer, leprosy, autism, type 2 diabetes mellitus and Alzheimer's disease. PARK2 primary transcript undergoes an extensive alternative splicing, which enhances transcriptomic diversification and protein diversity in tissues and cells. This review will provide an update of all human PARK2 alternative splice transcripts and isoforms presently known, and correlate them to those in rat and mouse, two common animal models for studying human disease genes. Alternative splicing relies upon a complex process that could be easily altered by both cis and trans-acting mutations. Although the contribution of PARK2 splicing in human disease remains to be fully explored, some evidences show disruption of this versatile form of genetic regulation may have pathological consequences.
    Current Genomics 06/2014; 15(3):203-16. DOI:10.2174/1389202915666140426003342 · 2.87 Impact Factor
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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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    ABSTRACT: Tumors frequently arise as a result of an acquired genomic instability and the subsequent evolution of neoplastic populations with variable genomes. A barrier to the study of the somatic genetics of human solid tumors in vivo is the presence of admixtures of non-neoplastic cells with normal genomes in patient samples. These can obscure the presence of somatic aberrations including mutations, homozygous deletions, and breakpoints in biopsies of interest. Furthermore, clinical samples frequently contain multiple neoplastic populations that cannot be distinguished by morphology. Consequently, it is difficult to determine whether mutations detected in a sample of interest are concurrent in a single clonal population or if they occur in distinct cell populations in the same sample. The advent of targeted therapies increases the selection for preexisting populations. However the asymmetric distribution of therapeutic targets in clonal populations provides a mechanism for the rapid evolution of resistant disease. Thus, there is a need to not only isolate tumor from normal cells, but to also enrich distinct populations of clonal neoplastic cells in order to apply genome technologies to identify clinically relevant genomic aberrations that drive disease in patients in vivo. To address this we have applied single and multiparameter DNA content based flow assays to the study of solid tumors. Our work has identified examples of clonal resistance to effective therapies. This includes androgen withdrawal in advanced prostate cancer. In addition we demonstrate examples of co-existing clonal populations with highly aberrant genomes and ploidies in a wide variety of solid tumors. We propose that clonal analysis of tumors, based on flow cytometry and high resolution genome analyses of purified neoplastic populations, provides a unique approach to the study of therapeutic responses and the evolution of resistance.
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