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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Parkinson disease (PARK) genes are somatically mutated in cutaneous melanoma
Rivka Inzelberg1, Yardena Samuels1, Esther Azizi1
1Department 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.
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.
Insights
Parkinson disease (PD) genes are somatically mutated in cutaneous melanoma (CM) tissue, suggesting shared pathways. Multiple PARK gene mutations were significantly more common in CM than in lung cancers.
Area of Science:
- Oncology
- Genetics
- Neurology
Background:
- Cutaneous melanoma (CM) incidence is higher in Parkinson disease (PD) patients.
- Parkinson disease (PD) is more common than expected in cutaneous melanoma (CM) cohorts.
- Investigating shared genetic factors between PD and CM is crucial.
Purpose of the Study:
- To determine if Parkinson disease (PD) genes are somatically mutated in cutaneous melanoma (CM) tissue.
- To explore potential shared molecular pathways between PD and CM.
- To compare the mutation patterns of PD genes in CM with those in lung cancers.
Main Methods:
- Whole-exome sequencing data from metastatic CM (n=246) were analyzed.
- Somatic mutations were cross-referenced with 15 known Parkinson disease (PARK) genes.
- Mutation frequencies and distributions were statistically compared between CM and lung cancer cohorts.
Main Results:
- Somatic mutations in 14 of 15 PARK genes were detected in CM.
- 48% of CM samples had at least one PARK mutation; 25% had multiple.
- PARK8 mutations exceeded the 95th percentile for mutation burden and sample prevalence.
- CM samples showed significantly more multiple PARK gene mutations than lung cancer types.
Conclusions:
- The increased frequency of somatic PARK gene mutations in CM suggests shared dysregulated pathways.
- These findings point to a potential molecular link between Parkinson disease and cutaneous melanoma.
- Further research into these shared pathways could inform therapeutic strategies.
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