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A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation.
Yanchus, Connor; Drucker, Kristen L; Kollmeyer, Thomas M; Tsai, Ricky; Winick-Ng, Warren; Liang, Minggao; Malik, Ahmad; Pawling, Judy; De Lorenzo, Silvana B; Ali, Asma; Decker, Paul A; Kosel, Matt L; Panda, Arijit; Al-Zahrani, Khalid N; Jiang, Lingyan; Browning, Jared W L; Lowden, Chris; Geuenich, Michael; Hernandez, J Javier; Gosio, Jessica T; Ahmed, Musaddeque; Loganathan, Sampath Kumar; Berman, Jacob; Trcka, Daniel; Michealraj, Kulandaimanuvel Antony; Fortin, Jerome; Carson, Brittany; Hollingsworth, Ethan W; Jacinto, Sandra; Mazrooei, Parisa; Zhou, Lily; Elia, Andrew; Lupien, Mathieu; He, Housheng Hansen; Murphy, Daniel J; Wang, Liguo; Abyzov, Alexej; Dennis, James W; Maass, Philipp G; Campbell, Kieran; Wilson, Michael D; Lachance, Daniel H; Wrensch, Margaret; Wiencke, John; Mak, Tak; Pennacchio, Len A; Dickel, Diane E; Visel, Axel; Wrana, Jeffrey; Taylor, Michael D.
Afiliación
  • Yanchus C; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Drucker KL; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Kollmeyer TM; Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • Tsai R; Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • Winick-Ng W; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Liang M; Max-Delbrück Centre for Molecular Medicine, Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group, 13092 Berlin, Germany.
  • Malik A; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Pawling J; Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • De Lorenzo SB; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Ali A; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Decker PA; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Kosel ML; Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • Panda A; Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • Al-Zahrani KN; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA.
  • Jiang L; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA.
  • Browning JWL; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA.
  • Lowden C; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Geuenich M; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Hernandez JJ; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Gosio JT; Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Ahmed M; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Loganathan SK; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Berman J; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Trcka D; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Michealraj KA; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Fortin J; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Carson B; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Hollingsworth EW; Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Jacinto S; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Mazrooei P; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Zhou L; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Elia A; Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Lupien M; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
  • He HH; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Murphy DJ; Department of Developmental and Cell Biology, University of California, Irvine, CA 92617, USA.
  • Wang L; Department of Developmental and Cell Biology, University of California, Irvine, CA 92617, USA.
  • Abyzov A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
  • Dennis JW; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Maass PG; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
  • Campbell K; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
  • Wilson MD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
  • Lachance DH; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Wrensch M; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
  • Wiencke J; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
  • Mak T; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Pennacchio LA; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, Scotland, UK.
  • Dickel DE; Cancer Research UK Beatson Institute, Glasgow G61 1BD, Scotland, UK.
  • Visel A; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA.
  • Wrana J; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA.
  • Taylor MD; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
Science ; 378(6615): 68-78, 2022 10 07.
Article en En | MEDLINE | ID: mdl-36201590
ABSTRACT
Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.
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Texto completo: 1 Colección: 01-internacional Asunto principal: Cromosomas Humanos Par 8 / Neoplasias Encefálicas / Glioma / Isocitrato Deshidrogenasa Límite: Animals / Humans Idioma: En Revista: Science Año: 2022 Tipo del documento: Article País de afiliación: Canadá
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Asunto principal: Cromosomas Humanos Par 8 / Neoplasias Encefálicas / Glioma / Isocitrato Deshidrogenasa Límite: Animals / Humans Idioma: En Revista: Science Año: 2022 Tipo del documento: Article País de afiliación: Canadá