title: A recurrent mutation in PARK2 is associated with familial lung cancer.
abstract: PARK2, a gene associated with Parkinson disease, is a tumor suppressor in human malignancies. Here, we show that c.823C>T (p.Arg275Trp), a germline mutation in PARK2, is present in a family with eight cases of lung cancer. The resulting amino acid change, p.Arg275Trp, is located in the highly conserved RING finger 1 domain of PARK2, which encodes an E3 ubiquitin ligase. Upon further analysis, the c.823C>T mutation was detected in three additional families affected by lung cancer. The effect size for PARK2 c.823C>T (odds ratio = 5.24) in white individuals was larger than those reported for variants from lung cancer genome-wide association studies. These data implicate this PARK2 germline mutation as a genetic susceptibility factor for lung cancer. Our results provide a rationale for further investigations of this specific mutation and gene for evaluation of the possibility of developing targeted therapies against lung cancer in individuals with PARK2 variants by compensating for the loss-of-function effect caused by the associated variation.
authors: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors: Donghai
authors: D
authors: Xiong
authors: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors: Yian
authors: Y
authors: Wang
authors: Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors: Elena
authors: E
authors: Kupert
authors: Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Baltimore, MD 20892, USA.
authors: Claire
authors: C
authors: Simpson
authors: Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors: Susan M
authors: SM
authors: Pinney
authors: College of Medicine, University of Toledo, Toledo, OH 43614, USA.
authors: Colette R
authors: CR
authors: Gaba
authors: Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors: Diptasri
authors: D
authors: Mandal
authors: Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors: Ann G
authors: AG
authors: Schwartz
authors: Mayo Clinic, Rochester, MN 55905, USA.
authors: Ping
authors: P
authors: Yang
authors: Mayo Clinic, Rochester, MN 55905, USA.
authors: Mariza
authors: M
authors: de Andrade
authors: Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03755, USA.
authors: Claudio
authors: C
authors: Pikielny
authors: Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03755, USA.
authors: Jinyoung
authors: J
authors: Byun
authors: Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03755, USA.
authors: Yafang
authors: Y
authors: Li
authors: Department of Ophthalmology and Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Dwight
authors: D
authors: Stambolian
authors: Baylor College of Medicine, Houston, TX 77030, USA.
authors: Margaret R
authors: MR
authors: Spitz
authors: Baylor College of Medicine, Houston, TX 77030, USA.
authors: Yanhong
authors: Y
authors: Liu
authors: Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03755, USA.
authors: Christopher I
authors: CI
authors: Amos
authors: Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Baltimore, MD 20892, USA.
authors: Joan E
authors: JE
authors: Bailey-Wilson
authors: Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors: Marshall
authors: M
authors: Anderson
authors: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: myou@mcw.edu.
authors: Ming
authors: M
authors: You
mesh_terms: D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D016017:Odds Ratio; D010375:Pedigree; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D017931:DNA Primers; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
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