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J Natl Cancer Inst. 2015 Dec 17;108(3). doi: 10.1093/jnci/djv340. Print 2016 Mar.

PARKIN Inactivation Links Parkinson's Disease to Melanoma.

Author information

1
Affiliations of authors: INSERM, U976, Centre de Recherche sur la Peau, Hôpital Saint Louis , Paris , France (HHH, JA, SM, LM, VD, NBS, MB, AB, CL, ND, NS); AP-HP, Hôpital Bichat Claude Bernard, Département de Génétique , Paris , France (HHH, CK, AT, BG, NS); Université Paris Diderot, Sorbonne Paris Cité , UMRS976, Paris , France (HHH, CK, JA, LM, NBS, MB, AB, LD, AT, BG, ND, NS); Université Paris 6, INSERM UMRS975, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, AP-HP , Paris , France (SL, AB); INSERM, U940, Laboratoire de Pharmacologie, Hôpital Saint Louis Paris , France (SM); AP-HP, Hôpital Bichat Claude Bernard, Service de Dermatologie , Paris , France (VD); AP-HP, Hôpital Saint Louis, Service de Dermatologie , Paris , France (NBS, MB, CL, ND); INSERM, CRB3, Département de Pathologie, Hôpital Bichat, AP-HP , Paris , France (LD); AP-HP, Hôpital Ambroise Paré, Service de Dermatologie , Boulogne Billancourt , France (PS); CHU Grenoble, Service de Dermatologie , Grenoble , France (MTL); Gustave Roussy, Service de Génétique, Département de Biopathologie , Villejuif , France (BBdP); Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580 , Heidelberg , Germany (RK); Department of Neurology, University Hospital of Würzburg , Würzburg , Germany (SK); Inserm UMR1037, Centre de Recherche en Cancérologie de Toulouse , Toulouse , France (NAA); Hôpital de l'Hôtel-Dieu, Service de Dermatologie , Lyon , France (LT); AP-HP, Groupe Pitié-Salpêtrière, Département de Génétique, Cytogénétique et Embryologie , Paris , France (AB).

Abstract

BACKGROUND:

Melanoma incidence is higher in patients affected by Parkinson's disease (PD) and vice versa, but the genetic link shared by both diseases is unknown. As PARK2 is both a tumor suppressor gene and frequently mutated in young onset PD, we evaluated the role of PARK2 in melanoma predisposition and progression.

METHODS:

An in-depth PARK2 gene dosage analysis and sequencing was performed on 512 French case patients and 562 healthy control patients, as well as sporadic tumors and melanoma cell lines. The frequency of genetic alterations was compared between case patients and control patients using two-sided Fisher's exact tests and odds ratio (OR) calculations. We used western blotting to determine PARKIN expression in melanocytes and melanoma cell lines and transfection followed by clonogenic assays to evaluate the effect of PARKIN expression on cellular proliferation. All statistical tests were two-sided.

RESULTS:

Germline PARK2 mutations (including copy number variations, splicing, and putative deleterious missense mutations) were present in 25 case patients but only four control patients (OR = 3.95, 95% confidence interval = 1.34 to 15.75). Copy number variations (CNVs) and loss of heterozygosity were present in 60% and 74%, respectively, of primary tumors. PARKIN protein was expressed in melanocytes but not in most melanoma cell lines, and its expression decreased following melanocyte transformation by oncogenic NRAS. Re-expression of PARKIN in melanoma cell lines resulted in a drastic reduction of cell proliferation and inhibition of PARKIN in melanocytes stimulated their proliferation.

CONCLUSION:

Our results show an important role for PARK2 as a tumor suppressor both in melanoma predisposition and progression, which could explain the epidemiological association of these diseases.

PMID:
26683220
DOI:
10.1093/jnci/djv340
[Indexed for MEDLINE]

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