Genetic Predisposition to Sporadic and Familial Multiple Myeloma
(2022) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- 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... (More) - 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.
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Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/b14ba5d5-8266-4343-89fc-7bb209205d33
- author
- Halvarsson, Britt-Marie LU
- supervisor
-
- Björn Nilsson LU
- Markus Hansson LU
- opponent
-
- Associate Professor Sommer Kristensen, Lasse, Department of Biomedicine, Aarhus University
- organization
- alternative title
- Genetisk predisposition för sporadiskt och familjärt multipelt myelom
- publishing date
- 2022
- type
- Thesis
- publication status
- published
- subject
- keywords
- multiple myeloma, genetics, inherited predisposition, familial multiple myeloma, GWAS, polygenic risk score
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2022:1
- pages
- 99 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/67325321548?pwd=Y0EvWnZDclpEOFJ1S3lQUzlKSHZvUT09
- defense date
- 2022-01-07 13:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-162-8
- language
- English
- LU publication?
- yes
- id
- b14ba5d5-8266-4343-89fc-7bb209205d33
- date added to LUP
- 2021-12-01 23:28:26
- date last changed
- 2024-05-17 11:33:35
@phdthesis{b14ba5d5-8266-4343-89fc-7bb209205d33,
abstract = {{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.<br/><br/>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.<br/><br/>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.<br/><br/>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. <br/>In Paper I, we identified a novel significant association with <i>ELL2</i>, and a border-line suggestive association with <i>TOM1</i>.<br/><br/>In Paper II and IV we collaborated internationally in GWAS meta-analyses and identified eight and six variants, respectively, in or near the genes <i>JARID2</i> (at 6p22.3), <i>ATG5</i> (6q21), <i>SMARCD3</i>, (7q36.1), <i>CCAT1</i> (8q24.21), <i>CDKN2A</i> (9p21.3), <i>WAC</i> (10p12.1), <i>RFWD3</i> (16q23.1), <i>PREX1</i> (20q13.13), <i>CEP120</i> (5q23.2), <i>POT1</i> (7q31.33), <i>CCDC71L</i> (7q22.3), <i>SP3</i> (2q31.1), <i>KLF2</i> (19p13.11) and <i>PRR14</i>/<i>RNF40</i> (16p11.2). The <i>TOM1</i> variant in Paper I replicated in these studies. The identified MM risk loci is estimated to explain a 20% of MM heritability.<br/><br/>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.<br/>}},
author = {{Halvarsson, Britt-Marie}},
isbn = {{978-91-8021-162-8}},
issn = {{1652-8220}},
keywords = {{multiple myeloma; genetics; inherited predisposition; familial multiple myeloma; GWAS; polygenic risk score}},
language = {{eng}},
number = {{2022:1}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Genetic Predisposition to Sporadic and Familial Multiple Myeloma}},
url = {{https://lup.lub.lu.se/search/files/110400703/Britt_Marie_Halvarsson_web.pdf}},
year = {{2022}},
}