Published February 13, 2021 | Version v1
Journal article Open

Characterization of rare germline variants in familial multiple myeloma

Authors/Creators

  • 1. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
  • 2. Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • 3. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
  • 4. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
  • 5. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. National Center for Tumor Diseases Heidelberg (NCT), Heidelberg, Germany.
  • 6. Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 7. University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • 8. Kempten Clinic, Kempten, Germany.
  • 9. José Carreras Center for Immuno and Gene Therapy, Department of Internal Medicine I, Saarland University Medical School, Homburg (Saar), Germany.
  • 10. Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
  • 11. Cedars Sinai Cancer Center, Los Angeles, CA, USA.
  • 12. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 13. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
  • 14. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. a.foersti@kitz-heidelberg.de. Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.

Description

Multiple myeloma (MM) is a malignancy of plasma cells, characterized by the presence of monoclonal
immunoglobulin, known as M protein1. MM is preceded by monoclonal gammopathy of undetermined significance (MGUS) which is also a precursor of immunoglobulin light chain (AL) amyloidosis. Previous studies have reported a 2- to 4-fold increased risk of MGUS or MM in first-degree relatives of MM or MGUS patients, suggesting the existence of inherited susceptibility. For many years, high-risk germline predisposing genes have been lacking for MM. However, recent sequencing efforts have proposed a few novel candidates, most notably loss-offunction (LoF) variants in the tumor suppressor gene DIS3 and in the histone demethylase gene KDM1A, and others as recently reviewed in detail in Pertesi et al. 
In addition to the suspected rare, high-penetrance variants, genome-wide association studies have identified over 20 common, low-penetrance variants associated with the risk of MM; these were estimated to account for about 15% of the familial MM risk.

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Additional details

Funding

European Commission
Chaperon - ERA Chair Position for Excellent Research in Oncology 856620