title: Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies.
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.
authors: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors: Selvaraju
authors: S
authors: Veeriah
authors: Barry S
authors: BS
authors: Taylor
authors: Shasha
authors: S
authors: Meng
authors: Fang
authors: F
authors: Fang
authors: Emrullah
authors: E
authors: Yilmaz
authors: Igor
authors: I
authors: Vivanco
authors: Manickam
authors: M
authors: Janakiraman
authors: Nikolaus
authors: N
authors: Schultz
authors: Aphrothiti J
authors: AJ
authors: Hanrahan
authors: William
authors: W
authors: Pao
authors: Marc
authors: M
authors: Ladanyi
authors: Chris
authors: C
authors: Sander
authors: Adriana
authors: A
authors: Heguy
authors: Eric C
authors: EC
authors: Holland
authors: Philip B
authors: PB
authors: Paty
authors: Paul S
authors: PS
authors: Mischel
authors: Linda
authors: L
authors: Liau
authors: Timothy F
authors: TF
authors: Cloughesy
authors: Ingo K
authors: IK
authors: Mellinghoff
authors: David B
authors: DB
authors: Solit
authors: Timothy A
authors: TA
authors: Chan
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D018628:Gene Dosage; D014644:Genetic Variation; D005838:Genotype; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics; D017434:Protein Structure, Tertiary; D014183:Transplantation, Heterologous; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein