Parkinson disease (PARK) genes are somatically mutated in cutaneous melanoma.
OBJECTIVE
To assess whether Parkinson disease (PD) genes are somatically mutated in cutaneous melanoma (CM) tissue, because CM occurs in patients with PD at higher rates than in the general population and PD is more common than expected in CM cohorts.


METHODS
We cross-referenced somatic mutations in metastatic CM detected by whole-exome sequencing with the 15 known PD (PARK) genes. We computed the empirical distribution of the sum of mutations in each gene (Smut) and of the number of tissue samples in which a given gene was mutated at least once (SSampl) for each of the analyzable genes, determined the 90th and 95th percentiles of the empirical distributions of these sums, and verified the location of PARK genes in these distributions. Identical analyses were applied to adenocarcinoma of lung (ADENOCA-LUNG) and squamous cell carcinoma of lung (SQUAMCA-LUNG). We also analyzed the distribution of the number of mutated PARK genes in CM samples vs the 2 lung cancers.


RESULTS
Somatic CM mutation analysis (n = 246) detected 315,914 mutations in 18,758 genes. Somatic CM mutations were found in 14 of 15 PARK genes. Forty-eight percent of CM samples carried ≥1 PARK mutation and 25% carried multiple PARK mutations. PARK8 mutations occurred above the 95th percentile of the empirical distribution for SMut and SSampl. Significantly more CM samples harbored multiple PARK gene mutations compared with SQUAMCA-LUNG (p = 0.0026) and with ADENOCA-LUNG (p < 0.0001).


CONCLUSIONS
The overrepresentation of somatic PARK mutations in CM suggests shared dysregulated pathways for CM and PD.
Department of Neurology (R.I.), Department of Dermatology (E.A.), Sackler Faculty of Medicine, Tel Aviv University; Center of Advanced Technologies in Rehabilitation (R.I.), Sheba Medical Center, Tel Hashomer; Department of Molecular Cell Biology (Y.S., N.Q.), Weizmann Institute of Science, Rehovot; The Sagol School of Neuroscience (L.I.), Tel Aviv University; Department of Physics of Complex Systems (E.D.), Weizmann Institute of Science, Rehovot; Department of Industrial Engineering and Management (E.S.), Ben Gurion University of the Negev, Beer Sheva; The Susanne Levy Gertner Oncogenetics Unit (E.F.), Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer; and the Sackler Faculty of Medicine (E.F.), Tel Aviv University, Israel.
Rivka
R
Inzelberg
Department of Neurology (R.I.), Department of Dermatology (E.A.), Sackler Faculty of Medicine, Tel Aviv University; Center of Advanced Technologies in Rehabilitation (R.I.), Sheba Medical Center, Tel Hashomer; Department of Molecular Cell Biology (Y.S., N.Q.), Weizmann Institute of Science, Rehovot; The Sagol School of Neuroscience (L.I.), Tel Aviv University; Department of Physics of Complex Systems (E.D.), Weizmann Institute of Science, Rehovot; Department of Industrial Engineering and Management (E.S.), Ben Gurion University of the Negev, Beer Sheva; The Susanne Levy Gertner Oncogenetics Unit (E.F.), Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer; and the Sackler Faculty of Medicine (E.F.), Tel Aviv University, Israel.
Yardena
Y
Samuels
Department of Neurology (R.I.), Department of Dermatology (E.A.), Sackler Faculty of Medicine, Tel Aviv University; Center of Advanced Technologies in Rehabilitation (R.I.), Sheba Medical Center, Tel Hashomer; Department of Molecular Cell Biology (Y.S., N.Q.), Weizmann Institute of Science, Rehovot; The Sagol School of Neuroscience (L.I.), Tel Aviv University; Department of Physics of Complex Systems (E.D.), Weizmann Institute of Science, Rehovot; Department of Industrial Engineering and Management (E.S.), Ben Gurion University of the Negev, Beer Sheva; The Susanne Levy Gertner Oncogenetics Unit (E.F.), Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer; and the Sackler Faculty of Medicine (E.F.), Tel Aviv University, Israel.
Esther
E
Azizi
Department of Neurology (R.I.), Department of Dermatology (E.A.), Sackler Faculty of Medicine, Tel Aviv University; Center of Advanced Technologies in Rehabilitation (R.I.), Sheba Medical Center, Tel Hashomer; Department of Molecular Cell Biology (Y.S., N.Q.), Weizmann Institute of Science, Rehovot; The Sagol School of Neuroscience (L.I.), Tel Aviv University; Department of Physics of Complex Systems (E.D.), Weizmann Institute of Science, Rehovot; Department of Industrial Engineering and Management (E.S.), Ben Gurion University of the Negev, Beer Sheva; The Susanne Levy Gertner Oncogenetics Unit (E.F.), Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer; and the Sackler Faculty of Medicine (E.F.), Tel Aviv University, Israel.
Nouar
N
Qutob
Department of Neurology (R.I.), Department of Dermatology (E.A.), Sackler Faculty of Medicine, Tel Aviv University; Center of Advanced Technologies in Rehabilitation (R.I.), Sheba Medical Center, Tel Hashomer; Department of Molecular Cell Biology (Y.S., N.Q.), Weizmann Institute of Science, Rehovot; The Sagol School of Neuroscience (L.I.), Tel Aviv University; Department of Physics of Complex Systems (E.D.), Weizmann Institute of Science, Rehovot; Department of Industrial Engineering and Management (E.S.), Ben Gurion University of the Negev, Beer Sheva; The Susanne Levy Gertner Oncogenetics Unit (E.F.), Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer; and the Sackler Faculty of Medicine (E.F.), Tel Aviv University, Israel.
Lilah
L
Inzelberg
Department of Neurology (R.I.), Department of Dermatology (E.A.), Sackler Faculty of Medicine, Tel Aviv University; Center of Advanced Technologies in Rehabilitation (R.I.), Sheba Medical Center, Tel Hashomer; Department of Molecular Cell Biology (Y.S., N.Q.), Weizmann Institute of Science, Rehovot; The Sagol School of Neuroscience (L.I.), Tel Aviv University; Department of Physics of Complex Systems (E.D.), Weizmann Institute of Science, Rehovot; Department of Industrial Engineering and Management (E.S.), Ben Gurion University of the Negev, Beer Sheva; The Susanne Levy Gertner Oncogenetics Unit (E.F.), Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer; and the Sackler Faculty of Medicine (E.F.), Tel Aviv University, Israel.
Eytan
E
Domany
Department of Neurology (R.I.), Department of Dermatology (E.A.), Sackler Faculty of Medicine, Tel Aviv University; Center of Advanced Technologies in Rehabilitation (R.I.), Sheba Medical Center, Tel Hashomer; Department of Molecular Cell Biology (Y.S., N.Q.), Weizmann Institute of Science, Rehovot; The Sagol School of Neuroscience (L.I.), Tel Aviv University; Department of Physics of Complex Systems (E.D.), Weizmann Institute of Science, Rehovot; Department of Industrial Engineering and Management (E.S.), Ben Gurion University of the Negev, Beer Sheva; The Susanne Levy Gertner Oncogenetics Unit (E.F.), Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer; and the Sackler Faculty of Medicine (E.F.), Tel Aviv University, Israel.
Edna
E
Schechtman
Department of Neurology (R.I.), Department of Dermatology (E.A.), Sackler Faculty of Medicine, Tel Aviv University; Center of Advanced Technologies in Rehabilitation (R.I.), Sheba Medical Center, Tel Hashomer; Department of Molecular Cell Biology (Y.S., N.Q.), Weizmann Institute of Science, Rehovot; The Sagol School of Neuroscience (L.I.), Tel Aviv University; Department of Physics of Complex Systems (E.D.), Weizmann Institute of Science, Rehovot; Department of Industrial Engineering and Management (E.S.), Ben Gurion University of the Negev, Beer Sheva; The Susanne Levy Gertner Oncogenetics Unit (E.F.), Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer; and the Sackler Faculty of Medicine (E.F.), Tel Aviv University, Israel.
Eitan
E
Friedman