Genetic Predisposition to Sporadic and Familial Multiple Myeloma

Britt-Marie Halvarsson

Research output: ThesisDoctoral Thesis (compilation)

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Multiple Myeloma (MM) is the second most common hematological malignancy. It is defined by an uncontrolled growth of plasma cells, usually in the bone marrow. Clinically it is complicated by hypercalcemia, renal failure, anaemia, and bone pain. Although recent advances in the treatment have extended survival and quality-of-life considerably, MM remains a fatal disease.

Since the 1920’s MM has been reported to aggregate in families (famililial MM). In first-degree relatives of MM patients there is a two to four-fold increased risk in developing MM, pointing at a possible inherited genetic aetiology in at least a subset of MM patients.

The overall aim of this thesis is to identify germline DNA sequence variants that predispose for Multiple Myeloma (MM), and it is based on four Papers.

In Paper I, II and IV, we performed case-control genome-wide association studies (GWASs) to identify germline single nucleotide polymorphisms (SNPs) and small insertions/deletions (INDELs) that associate with MM risk.
In Paper I, we identified a novel significant association with ELL2, and a border-line suggestive association with TOM1.

In Paper II and IV we collaborated internationally in GWAS meta-analyses and identified eight and six variants, respectively, in or near the genes JARID2 (at 6p22.3), ATG5 (6q21), SMARCD3, (7q36.1), CCAT1 (8q24.21), CDKN2A (9p21.3), WAC (10p12.1), RFWD3 (16q23.1), PREX1 (20q13.13), CEP120 (5q23.2), POT1 (7q31.33), CCDC71L (7q22.3), SP3 (2q31.1), KLF2 (19p13.11) and PRR14/RNF40 (16p11.2). The TOM1 variant in Paper I replicated in these studies. The identified MM risk loci is estimated to explain a 20% of MM heritability.

In Paper III, we performed SNP microarray and whole-exome sequencing analysis on 38 cases of familial MM. Constructing polygenic risk scores, we found direct evidence for a polygenic aetiology in familial MM, and estimated that about one-third of familial MM cases were associated with an enrichment of common risk variants identified by GWAS. In Paper IV, we extended our polygenic risk scores with newly identified risk variants, and again observed an enrichment of risk variants in familial cases.
Translated title of the contributionGenetisk predisposition för sporadiskt och familjärt multipelt myelom
Original languageEnglish
Awarding Institution
  • Department of Laboratory Medicine
  • Nilsson, Björn, Supervisor
  • Hansson, Markus, Assistant supervisor
Award date2022 Jan 7
Place of PublicationLund
ISBN (Print)978-91-8021-162-8
Publication statusPublished - 2022

Bibliographical note

Defence details
Date: 2022-01-07
Time: 13:00
Place: Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom:
External reviewer(s)
Name: Sommer Kristensen, Lasse
Title: Associate Professor
Affiliation: Department of Biomedicine, Aarhus University

Subject classification (UKÄ)

  • Medical Genetics
  • Bioinformatics and Systems Biology
  • Cancer and Oncology

Free keywords

  • multiple myeloma
  • genetics
  • inherited predisposition
  • familial multiple myeloma
  • GWAS
  • polygenic risk score


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