Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies.
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.
Veeriah
Selvaraju
S
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Taylor
Barry S
BS
Meng
Shasha
S
Fang
Fang
F
Yilmaz
Emrullah
E
Vivanco
Igor
I
Janakiraman
Manickam
M
Schultz
Nikolaus
N
Hanrahan
Aphrothiti J
AJ
Pao
William
W
Ladanyi
Marc
M
Sander
Chris
C
Heguy
Adriana
A
Holland
Eric C
EC
Paty
Philip B
PB
Mischel
Paul S
PS
Liau
Linda
L
Cloughesy
Timothy F
TF
Mellinghoff
Ingo K
IK
Solit
David B
DB
Chan
Timothy A
TA
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
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein