Author Affiliations: Department of Basic Medical Sciences, Western University of Health Sciences, Lebanon (Dr Kisby), Global Health Center, Center for Research on Occupational and Environmental Toxicology, and Department of Neurology, Oregon Health & Science University, Portland (Dr Spencer).
Kareus and colleagues1 propose genetic links to explain an association between Parkinson disease (PD plus other parkinsonian disorders) and certain cancers, specifically melanoma and prostate cancer, across 3 generations in Utah. Closely knit populations, such as those in Utah, might also share etiologically relevant transgenerational exposures; witness Guam parkinsonism-dementia, which associates with foods containing the cycad toxin cycasin, the glucoside of methylazoxymethanol.2 The carcinogenic and neurotoxic properties of methylazoxymethanol are both mediated by DNA damage, changes in microRNA expression, and gene perturbation, the outcome ranging from proliferation for cycling cells (tumorigenesis) to degeneration for postmitotic neurons.3 Pathways in cancer, melanogenesis, and prostate cancer are 3 of the top 9 perturbed cell-signaling pathways in the brains of mice treated systemically with methylazoxymethanol.4 Methylazoxymethanol disrupts the PI3K-AKT-mTOR pathway, which is implicated in both melanogenesis and prostate cancer.5 The methylazoxymethanol metabolite formaldehyde, which is elevated in prostate cancer,6 is a member of the 1-carbon pool, use of which is impacted by the enzyme activity of methylenetetrahydrofolate reductase (MHTFR), and MTHFR polymorphisms are linked to the risk for PD, prostate cancer, and skin cancer, including melanoma.7-9
Kisby GE, Spencer PS. Parkinsonism and Cancer. JAMA Neurol. 2013;70(3):414–415. doi:10.1001/jamaneurol.2013.1283
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