Deciphering the genetics and mechanisms of predisposition to multiple myeloma.

Autor: Went M; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK., Duran-Lozano L; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.; Lund Stem Cell Center, Lund University, SE-221 84, Lund, Sweden., Halldorsson GH; deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland., Gunnell A; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK., Ugidos-Damboriena N; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.; Lund Stem Cell Center, Lund University, SE-221 84, Lund, Sweden., Law P; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK., Ekdahl L; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.; Lund Stem Cell Center, Lund University, SE-221 84, Lund, Sweden., Sud A; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK., Thorleifsson G; deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland., Thodberg M; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.; Lund Stem Cell Center, Lund University, SE-221 84, Lund, Sweden., Olafsdottir T; deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland., Lamarca-Arrizabalaga A; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.; Lund Stem Cell Center, Lund University, SE-221 84, Lund, Sweden., Cafaro C; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.; Lund Stem Cell Center, Lund University, SE-221 84, Lund, Sweden., Niroula A; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.; Lund Stem Cell Center, Lund University, SE-221 84, Lund, Sweden., Ajore R; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.; Lund Stem Cell Center, Lund University, SE-221 84, Lund, Sweden., Lopez de Lapuente Portilla A; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.; Lund Stem Cell Center, Lund University, SE-221 84, Lund, Sweden., Ali Z; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.; Lund Stem Cell Center, Lund University, SE-221 84, Lund, Sweden., Pertesi M; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.; Lund Stem Cell Center, Lund University, SE-221 84, Lund, Sweden., Goldschmidt H; Department of Internal Medicine V, University of Heidelberg, 69120, Heidelberg, Germany., Stefansdottir L; deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland., Kristinsson SY; Landspitali, National University Hospital of Iceland, IS-101, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, IS-101, Reykjavik, Iceland., Stacey SN; deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland., Love TJ; Landspitali, National University Hospital of Iceland, IS-101, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, IS-101, Reykjavik, Iceland., Rognvaldsson S; Landspitali, National University Hospital of Iceland, IS-101, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, IS-101, Reykjavik, Iceland., Hajek R; University Hospital Ostrava and University of Ostrava, Ostrava, Czech Republic., Vodicka P; Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic., Pettersson-Kymmer U; Department of Integrative Medical Biology, Umeå University, SE-901 87, Umeå, Sweden., Späth F; Department of Radiation Sciences, Umeå University, SE-901 87, Umeå, Sweden., Schinke C; Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA., Van Rhee F; Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA., Sulem P; deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland., Ferkingstad E; deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland., Hjorleifsson Eldjarn G; deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland., Mellqvist UH; Southern Älvsborg Hospital, SE-501 82, Borås, Sweden., Jonsdottir I; deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland., Morgan G; Perlmutter Cancer Center, Langone Health, New York University, New York, NY, USA., Sonneveld P; Department of Hematology, Erasmus MC Cancer Institute, 3075 EA, Rotterdam, The Netherlands., Waage A; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Box 8905, N-7491, Trondheim, Norway., Weinhold N; Department of Internal Medicine V, University of Heidelberg, 69120, Heidelberg, Germany.; German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany., Thomsen H; MSB Medical School Berlin, Berlin, Germany., Försti A; German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.; Hopp Children's Cancer Center, Heidelberg, Germany., Hansson M; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden.; Section of Hematology, Sahlgrenska University Hospital, Gothenburg, SE-413 45, Sweden.; Skåne University Hospital, SE-221 85, Lund, Sweden., Juul-Vangsted A; Department of Haematology, University Hospital of Copenhagen at Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark., Thorsteinsdottir U; deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, IS-101, Reykjavik, Iceland., Hemminki K; German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.; Faculty of Medicine in Pilsen, Charles University, 30605, Pilsen, Czech Republic., Kaiser M; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK., Rafnar T; deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland., Stefansson K; deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, IS-101, Reykjavik, Iceland., Houlston R; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK. richard.houlston@icr.ac.uk., Nilsson B; Department of Laboratory Medicine, Lund University, SE-221 84, Lund, Sweden. bjorn.nilsson@med.lu.se.; Lund Stem Cell Center, Lund University, SE-221 84, Lund, Sweden. bjorn.nilsson@med.lu.se.; Broad Institute, 415 Main Street, Cambridge, MA, 02142, USA. bjorn.nilsson@med.lu.se.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 05; Vol. 15 (1), pp. 6644. Date of Electronic Publication: 2024 Aug 05.
DOI: 10.1038/s41467-024-50932-7
Abstrakt: Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.
(© 2024. The Author(s).)
Databáze: MEDLINE
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