Cancer and Neurodegeneration: Between the Devil and the Deep Blue Sea

Cancer and neurodegeneration are often thought of as disease mechanisms at opposite ends of a spectrum; one due to enhanced resistance to cell death and the other due to premature cell death. There is now accumulating evidence to link these two disparate processes. An increasing number of genetic studies add weight to epidemiological evidence suggesting that sufferers of a neurodegenerative disorder have a reduced incidence for most cancers, but an increased risk for other cancers. Many of the genes associated with either cancer and/or neurodegeneration play a central role in cell cycle control, DNA repair, and kinase signalling. However, the links between these two families of diseases remain to be proven. In this review, we discuss recent and sometimes as yet incomplete genetic discoveries that highlight the overlap of molecular pathways implicated in cancer and neurodegeneration.

[1]  F. Dammacco,et al.  Targeted therapies in cancer , 2018, Surgery (Oxford).

[2]  N. Wood,et al.  Mitophagy and Parkinson's disease: The PINK1–parkin link , 2011, Biochimica et biophysica acta.

[3]  M. S. Luciano,et al.  LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease , 2010, Movement disorders : official journal of the Movement Disorder Society.

[4]  P. Kinnunen CANCER LINKED TO ALZHEIMER DISEASE BUT NOT VASCULAR DEMENTIA , 2010, Neurology.

[5]  M. Hetman,et al.  Neurotoxic mechanisms of DNA damage: focus on transcriptional inhibition , 2010, Journal of neurochemistry.

[6]  Nicholas W Wood,et al.  Genome-wide association studies: the key to unlocking neurodegeneration? , 2010, Nature Neuroscience.

[7]  T. Chan,et al.  Genetic determinants at the interface of cancer and neurodegenerative disease , 2010, Oncogene.

[8]  Oliver Kaut,et al.  Methylation Regulates Alpha-Synuclein Expression and Is Decreased in Parkinson's Disease Patients' Brains , 2010, The Journal of Neuroscience.

[9]  L. Mascitelli,et al.  FAMILY HISTORY OF MELANOMA AND PARKINSON DISEASE RISK , 2010, Neurology.

[10]  T. Chan,et al.  The familial Parkinson Disease gene PARK2 is a multisite tumor suppressor on chromosome 6q25.2-27 that regulates cyclin E , 2010, Cell cycle.

[11]  N. Wood,et al.  Targeting mitochondrial dysfunction in neurodegenerative disease: Part II , 2010, Expert opinion on therapeutic targets.

[12]  N. Wood,et al.  Targeting mitochondrial dysfunction in neurodegenerative disease: Part I , 2010, Expert opinion on therapeutic targets.

[13]  K. Garber Parkinson's disease and cancer: the unexplored connection. , 2010, Journal of the National Cancer Institute.

[14]  J. Dunys,et al.  p53 Is Regulated by and Regulates Members of the γ-Secretase Complex , 2010, Neurodegenerative Diseases.

[15]  S. Armstrong,et al.  HELP for AML: methylation profiling opens new avenues. , 2010, Cancer cell.

[16]  David A. Bennett,et al.  Is there a link between cancer and Alzheimer disease? , 2010, Neurology.

[17]  C. Hooper,et al.  Inhibiting p53 pathways in microglia attenuates microglial‐evoked neurotoxicity following exposure to Alzheimer peptides , 2010, Journal of neurochemistry.

[18]  F. Checler,et al.  A novel parkin-mediated transcriptional function links p53 to familial Parkinson’s disease , 2010, Cell cycle.

[19]  C. Sander,et al.  Somatic mutations of the Parkinson's disease–associated gene PARK2 in glioblastoma and other human malignancies , 2010, Nature Genetics.

[20]  E. Schernhammer,et al.  Parkinson’s disease and cancer risk: a systematic review and meta-analysis , 2010, Cancer Causes & Control.

[21]  M. Vitek,et al.  p53-dependent control of transactivation of the Pen2 promoter by presenilins , 2009, Journal of Cell Science.

[22]  Patrick M. Abou-Sleiman,et al.  Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease , 2009, Nature Cell Biology.

[23]  I. Yeh,et al.  Genome‐wide associations studies for melanoma and nevi , 2009, Pigment cell & melanoma research.

[24]  R. Inzelberg,et al.  The particular relationship between Parkinson’s disease and malignancy: a focus on skin cancers , 2009, Journal of Neural Transmission.

[25]  David Yeates,et al.  Cancer in patients with motor neuron disease, multiple sclerosis and Parkinson's disease: record linkage studies , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[26]  J. Malvehy,et al.  Genome-wide association study identifies three loci associated with melanoma risk , 2009, Nature Genetics.

[27]  T. Spector,et al.  Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi , 2009, Nature Genetics.

[28]  C. Lendon,et al.  A common biological mechanism in cancer and Alzheimer's disease? , 2009, Current Alzheimer research.

[29]  Jiali Han,et al.  Genetic determinants of hair color and parkinson's disease risk , 2009, Annals of neurology.

[30]  D. Hernandez,et al.  Characterization of PLA2G6 as a locus for dystonia‐parkinsonism , 2008, Annals of neurology.

[31]  J. Fitzgerald,et al.  Emerging pathways in genetic Parkinson’s disease: Autosomal‐recessive genes in Parkinson’s disease – a common pathway? , 2008, The FEBS journal.

[32]  Michael J. Devine,et al.  Emerging pathways in genetic Parkinson’s disease: tangles, Lewy bodies and LRRK2 , 2008, The FEBS journal.

[33]  M. Farrer,et al.  ARE PARKINSON DISEASE PATIENTS PROTECTED FROM SOME BUT NOT ALL CANCERS? , 2008, Neurology.

[34]  Amy E. Hawkins,et al.  DNA sequencing of a cytogenetically normal acute myeloid leukemia genome , 2008, Nature.

[35]  Nilanjan Chatterjee,et al.  Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway. , 2008, Carcinogenesis.

[36]  J. Staropoli,et al.  Tumorigenesis and neurodegeneration: two sides of the same coin? , 2008, BioEssays : news and reviews in molecular, cellular and developmental biology.

[37]  Pier Paolo Pandolfi,et al.  Tenets of PTEN Tumor Suppression , 2008, Cell.

[38]  J. Yates,et al.  Effects of Cu/Zn superoxide dismutase on estrogen responsiveness and oxidative stress in human breast cancer cells. , 2008, Molecular endocrinology.

[39]  A. Hofman,et al.  Cyclin-dependent kinase 5 is associated with risk for Alzheimer’s disease in a Dutch population-based study , 2008, Journal of Neurology.

[40]  G. Tsangaris,et al.  The ATM gene and ataxia telangiectasia. , 2008, Anticancer research.

[41]  A. Geller,et al.  Increased cancer risk for individuals with a family history of prostate cancer, colorectal cancer, and melanoma and their associated screening recommendations and practices , 2008, Cancer Causes & Control.

[42]  M. Rajadhyaksha,et al.  An Unusual Member of the Cdk Family: Cdk5 , 2008, Cellular and Molecular Neurobiology.

[43]  A. Singleton,et al.  Kinase signaling pathways as potential targets in the treatment of Parkinson’s disease , 2007, Expert review of proteomics.

[44]  Rivka Inzelberg,et al.  Are Parkinson disease patients protected from some but not all cancers? , 2007, Neurology.

[45]  J. Olsen,et al.  Treatment with levodopa and risk for malignant melanoma , 2007, Movement disorders : official journal of the Movement Disorder Society.

[46]  A. Lang,et al.  Deciphering the role of heterozygous mutations in genes associated with parkinsonism , 2007, The Lancet Neurology.

[47]  J. Buring,et al.  A Prospective Cohort Study of Cancer Incidence Following the Diagnosis of Parkinson's Disease , 2007, Cancer Epidemiology Biomarkers & Prevention.

[48]  R. Szargel,et al.  Phosphorylation of Parkin by the Cyclin-dependent Kinase 5 at the Linker Region Modulates Its Ubiquitin-Ligase Activity and Aggregation* , 2007, Journal of Biological Chemistry.

[49]  M. Pallàs,et al.  Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium-induced apoptosis in neurons , 2007, Neuroscience.

[50]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[51]  Peter A. Jones,et al.  The Epigenomics of Cancer , 2007, Cell.

[52]  F. Viader,et al.  Breast cancer and motor neuron disease: Clinical study of seven cases , 2007, Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.

[53]  P. Baade,et al.  Mortality due to Amyotrophic Lateral Sclerosis and Parkinson’s Disease among Melanoma Patients , 2006, Neuroepidemiology.

[54]  D. Sabatini,et al.  Stress and mTORture signaling , 2006, Oncogene.

[55]  N. Quinn,et al.  A heterozygous effect for PINK1 mutations in Parkinson's disease? , 2006, Annals of neurology.

[56]  N. Rahman,et al.  ATM and breast cancer susceptibility , 2006, Oncogene.

[57]  Jan Gründemann,et al.  Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase , 2006, Nature Genetics.

[58]  J. Olsen,et al.  Malignant Melanoma and Other Types of Cancer Preceding Parkinson Disease , 2006, Epidemiology.

[59]  Robert H. Brown,et al.  Molecular biology of amyotrophic lateral sclerosis: insights from genetics , 2006, Nature Reviews Neuroscience.

[60]  D. Kaplan,et al.  The p53 family in nervous system development and disease , 2006, Journal of neurochemistry.

[61]  S. Rosso,et al.  Melanoma, Parkinson's disease and levodopa: causal or spurious link? A review of the literature , 2006, Melanoma research.

[62]  F. Gumy-Pause,et al.  ATM variants and predisposition to childhood T-lineage acute lymphoblastic leukaemia , 2006, Leukemia.

[63]  T. Mak,et al.  Tumours and tremors: how PTEN regulation underlies both , 2006, British Journal of Cancer.

[64]  H. Storm,et al.  Cancer risk among patients with multiple sclerosis: A population‐based register study , 2006, International journal of cancer.

[65]  A. Levine,et al.  p53 tumor suppressor protein regulates the levels of huntingtin gene expression , 2006, Oncogene.

[66]  L. Travis,et al.  Amyotrophic Lateral Sclerosis Mortality in 1.9 Million US Cancer Survivors , 2005, Neuroepidemiology.

[67]  P. Boyle,et al.  Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. , 2005, European journal of cancer.

[68]  W. Xiao,et al.  Molecular basis of ataxia telangiectasia and related diseases , 2005, Acta Pharmacologica Sinica.

[69]  S. Snyder,et al.  p53 Mediates Cellular Dysfunction and Behavioral Abnormalities in Huntington’s Disease , 2005, Neuron.

[70]  T. Dawson,et al.  To die or grow: Parkinson's disease and cancer , 2005, Trends in Neurosciences.

[71]  Jeffrey P. MacKeigan,et al.  Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance , 2005, Nature Cell Biology.

[72]  T. Mak,et al.  DJ-1, a novel regulator of the tumor suppressor PTEN. , 2005, Cancer cell.

[73]  K. Offit,et al.  Hereditary cancer predisposition syndromes. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[74]  J. Olsen,et al.  Atypical cancer pattern in patients with Parkinson's disease , 2004, British Journal of Cancer.

[75]  Yosef Shiloh,et al.  Ataxia-telangiectasia and the ATM gene: Linking neurodegeneration, immunodeficiency, and cancer to cell cycle checkpoints , 1996, Journal of Clinical Immunology.

[76]  P. Boyle,et al.  Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical naevi. , 2005, European journal of cancer.

[77]  P. Boyle,et al.  Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. , 2005, European journal of cancer.

[78]  Thomas Meitinger,et al.  Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology , 2004, Neuron.

[79]  Andrew Lees,et al.  Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease , 2004, Neuron.

[80]  Zigang Dong,et al.  Post-translational modification of p53 in tumorigenesis , 2004, Nature Reviews Cancer.

[81]  Y. Hod Differential control of apoptosis by DJ‐1 in prostate benign and cancer cells , 2004, Journal of cellular biochemistry.

[82]  Fang Wang,et al.  Parkin gene alterations in hepatocellular carcinoma , 2004, Genes, chromosomes & cancer.

[83]  R. Nussbaum,et al.  Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1 , 2004, Science.

[84]  H. Storm,et al.  Familial clustering of Hodgkin lymphoma and multiple sclerosis. , 2004, Journal of the National Cancer Institute.

[85]  C. Croce,et al.  Alterations of the Tumor Suppressor Gene Parkin in Non-Small Cell Lung Cancer , 2004, Clinical Cancer Research.

[86]  Sandya Liyanarachchi,et al.  Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: Amplification discloses overexpression of APP, ETS2, and ERG genes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[87]  M. Pallàs,et al.  Inhibition of CDKs: A Strategy for Preventing Kainic Acid‐Induced Apoptosis in Neurons , 2003, Annals of the New York Academy of Sciences.

[88]  C. Klein,et al.  Alterations in the common fragile site gene Parkin in ovarian and other cancers , 2003, Oncogene.

[89]  Y. Hod,et al.  Proteomic profiling drug-induced apoptosis in non-small cell lung carcinoma: identification of RS/DJ-1 and RhoGDIalpha. , 2003, Cancer research.

[90]  David I. Smith,et al.  Characterization of FRA6E and its potential role in autosomal recessive juvenile parkinsonism and ovarian cancer , 2003, Genes, chromosomes & cancer.

[91]  Charis Eng,et al.  PTEN: One Gene, Many Syndromes , 2003, Human mutation.

[92]  Jacqueline Whetteckey,et al.  Malignant melanoma and levodopa in Parkinson's disease: causality or coincidence? , 2003, Parkinsonism & related disorders.

[93]  C. Croce,et al.  Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25–q27 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[94]  E. Monaco,et al.  Cyclin-dependent kinase inhibitors: cancer killers to neuronal guardians. , 2003, Current medicinal chemistry.

[95]  Lucia Migliore,et al.  Genetic and environmental factors in cancer and neurodegenerative diseases. , 2002, Mutation research.

[96]  Patrizia Rizzu,et al.  Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism , 2002, Science.

[97]  Miguel A Hernán,et al.  A meta‐analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease , 2002, Annals of neurology.

[98]  David E. Misek,et al.  Proteomics-based identification of RS/DJ-1 as a novel circulating tumor antigen in breast cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[99]  Jeffrey D. Rothstein,et al.  From charcot to lou gehrig: deciphering selective motor neuron death in als , 2001, Nature Reviews Neuroscience.

[100]  Yusuke Nakamura,et al.  Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway , 2001, Oncogene.

[101]  O. Nanni,et al.  Lymphomas and multiple sclerosis in a multicenter case-control study. , 2001, Epidemiology.

[102]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[103]  Shinsei Minoshima,et al.  Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase , 2000, Nature Genetics.

[104]  J. Klijn,et al.  ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. , 2000, American journal of human genetics.

[105]  J. Levine,et al.  Surfing the p53 network , 2000, Nature.

[106]  K Fenger,et al.  Significantly lower incidence of cancer among patients with Huntington disease , 1999, Cancer.

[107]  V. Tron,et al.  Expression of cell cycle regulators in human cutaneous malignant melanoma. , 1999, Melanoma research.

[108]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[109]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[110]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[111]  John Hardy,et al.  Amyloid, the presenilins and Alzheimer's disease , 1997, Trends in Neurosciences.

[112]  T. Taira,et al.  DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. , 1997, Biochemical and biophysical research communications.

[113]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.

[114]  B. Colombo,et al.  Multiple sclerosis and cancer in Norway. A retrospective cohort study , 1995, Journal of Neuroimmunology.

[115]  S. Franceschi,et al.  Risk of cutaneous melanoma associated with a family history of the disease , 1995, International journal of cancer.

[116]  J. Olsen,et al.  Occurrence of different cancers in patients with Parkinson's disease , 1995, BMJ.

[117]  E. Mandelkow,et al.  Abnormal Alzheimer‐like phosphorylation of tau‐protein by cyclin‐dependent kinases cdk2 and cdk5 , 1993, FEBS letters.

[118]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[119]  L. Strong,et al.  Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. , 1990, Science.

[120]  J. Waterhouse,et al.  Gliomatous transformation and demyelinating diseases. , 1980, Brain : a journal of neurology.

[121]  L. Brain,et al.  Motor neurone disease as a manifestation of neoplasm (with a note on the course of classical motor neurone disease). , 1965, Brain : a journal of neurology.