title: Cancer risk in DM1 is sex-related and linked to miRNA-200/141 downregulation.
abstract: OBJECTIVE
  Describe the incidence of cancer in a large cohort of patients with myotonic dystrophy type 1 (DM1) and to unravel the underlying molecular mechanisms.
  
  
  METHODS
  Standardized incidence ratios (SIRs) were calculated in the Gipuzkoa DM1 cohort (1985-2013), dividing observed numbers by expected numbers for all cancers combined and stratified by sex. An estimation of the expected incidence was achieved by multiplying the age- and sex-specific incidence rates from the Basque population cancer registry by the person-years observed in the study cohort. Large-scale gene expression of peripheral blood mononuclear cell samples derived from 10 individuals with DM1 (5 men, 5 women) and 10 healthy matched controls was analyzed by the Human Gene 1.0 ST Affymetrix microarray.
  
  
  RESULTS
  During 18,796 person-years of follow-up, corresponding to 424 patients with DM1, we observed 70 cancers in 62 patients giving a 1.81-fold risk (95% confidence interval [CI] 1.37-2.36), which was stronger in women than in men. Ovary (SIR 8.33, 95% CI 1.72-24.31) and endometrium (SIR 6.86, 95% CI 2.23-16.02) in women and thyroid (SIR 23.33, 95% CI 9.38-48.08) and brain (SIR 9.80, 95% CI 3.18-22.88) in both sexes were tumor sites with significantly higher risks in DM1. There were differences in gene expression between healthy controls and patients with DM1 and between men and women with DM1; all patients with DM1 combined and female patients with DM1 displayed significant downregulation of the microRNA (miRNA)-200c/141 tumor suppressor family.
  
  
  CONCLUSIONS
  Oncologic risk is increased in DM1, especially in women and for gynecologic, brain, and thyroid cancer. Expression of the miRNA-200/miRNA-141 tumor suppressor family is decreased in women with DM1.
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain.
authors: Roberto
authors: R
authors: Fernández-Torrón
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain.
authors: Mikel
authors: M
authors: García-Puga
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain.
authors: José-Ignacio
authors: JI
authors: Emparanza
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain.
authors: Miren
authors: M
authors: Maneiro
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain.
authors: Ana-María
authors: AM
authors: Cobo
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain.
authors: Juan-José
authors: JJ
authors: Poza
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain.
authors: Juan-Bautista
authors: JB
authors: Espinal
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain.
authors: Miren
authors: M
authors: Zulaica
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain.
authors: Irune
authors: I
authors: Ruiz
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain.
authors: Loreto
authors: L
authors: Martorell
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain.
authors: David
authors: D
authors: Otaegui
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain.
authors: Ander
authors: A
authors: Matheu
authors: From the Neuromuscular Unit, Neurology Department (R.F.-T., M.M., J.-J.P., J.-B.E., A.L.d.M.), and Department of Pathology (I.R.), Donostia Universitary Hospital, San Sebastian; Neurosciences Area (R.F.-T., M.Z., D.O., A.L.d.M.) and Oncology Area (M.G.-P., A.M.), Biodonostia Institute, San Sebastian; Center for Biomedical Research Network in Neurodegenerative Diseases (CIBERNED) (R.F.-T., A.L.d.M.), Institute Carlos III, Ministry of Economy and Competitiveness; Clinical Epidemiology Unit (J.-I.E.), Donostia Universitary Hospital, CIBER-ESP, San Sebastian, Spain; Neuromuscular Area (A.-M.C.), AP-HP Hôpital Marin de Hendaye, France; Molecular Genetics Section (L.M.), Hospital Sant Joan de Deu, Barcelona; and Department of Neurosciences (A.L.d.M.), University of the Basque Country, UPV/EHU, San Sebastian, Spain. adolfo.lopezdemunainarregui@osakidetza.eus.
authors: Adolfo
authors: A
authors: López de Munain
mesh_terms: D000328:Adult; D015153:Blotting, Western; D015536:Down-Regulation; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D015994:Incidence; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009223:Myotonic Dystrophy / Q000150:complications / Q000453:epidemiology* / Q000378:metabolism; D009369:Neoplasms / Q000453:epidemiology* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D012306:Risk; D012737:Sex Factors
chemical_list: C533895:MIRN141 microRNA, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger