Multiple myeloma (MM) is a plasma cell malignancy whereby a single clone of plasma cells over-propagates in the bone marrow, resulting in the increased production of monoclonal immunoglobulin. While the complex genetic architecture of MM is well characterized, much less is known about germline variants predisposing to MM. Genome-wide sequencing approaches in MM families have started to identify rare high-penetrance coding risk alleles. In addition, genome-wide association studies have discovered several common low-penetrance risk alleles, which are mainly located in the non-coding genome. Here, we further explored the genetic basis in familial MM within the non-coding genome in whole-genome sequencing data. We prioritized and characterized 150 upstream, 5' untranslated region (UTR) and 3' UTR variants from 14 MM families, including 20 top-scoring variants. These variants confirmed previously implicated biological pathways in MM development. Most importantly, protein network and pathway enrichment analyses also identified 10 genes involved in mitogen-activated protein kinase (MAPK) signaling pathways, which have previously been established as important MM pathways.

Bioinformatics and Omics Data Analytics German Cancer Research Center 69120 Heidelberg Germany

Cedars Sinai Cancer Center Los Angeles CA 90048 USA

Computational Oncology Molecular Precision Oncology Program National Center for Tumor Diseases 69120 Heidelberg Germany

Department of Internal Medicine 5 University of Heidelberg 69120 Heidelberg Germany

Department of Medical Oncology Jerome Lipper Multiple Myeloma Center Dana Farber Cancer Institute Boston MA 02115 USA

Division of Cancer Epidemiology German Cancer Research Center 69120 Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center 69120 Heidelberg Germany

Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague 323 00 Pilsen Czech Republic

Harvard Medical School Boston MA 02115 USA

Hopp Children's Cancer Center 69120 Heidelberg Germany

Institute of Bioinformatics International Technology Park Bangalore 560066 India

Manipal Academy of Higher Education Manipal 576104 India

National Center for Tumor Diseases Heidelberg 69120 Heidelberg Germany

University Medical Center Groningen University of Groningen 9712 Groningen The Netherlands

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