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Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma

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 varia...

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Autores principales: Niazi, Yasmeen, Paramasivam, Nagarajan, Blocka, Joanna, Kumar, Abhishek, Huhn, Stefanie, Schlesner, Matthias, Weinhold, Niels, Sijmons, Rolf, De Jong, Mirjam, Durie, Brian, Goldschmidt, Hartmut, Hemminki, Kari, Försti, Asta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9818386/
https://www.ncbi.nlm.nih.gov/pubmed/36611892
http://dx.doi.org/10.3390/cells12010096
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author Niazi, Yasmeen
Paramasivam, Nagarajan
Blocka, Joanna
Kumar, Abhishek
Huhn, Stefanie
Schlesner, Matthias
Weinhold, Niels
Sijmons, Rolf
De Jong, Mirjam
Durie, Brian
Goldschmidt, Hartmut
Hemminki, Kari
Försti, Asta
author_facet Niazi, Yasmeen
Paramasivam, Nagarajan
Blocka, Joanna
Kumar, Abhishek
Huhn, Stefanie
Schlesner, Matthias
Weinhold, Niels
Sijmons, Rolf
De Jong, Mirjam
Durie, Brian
Goldschmidt, Hartmut
Hemminki, Kari
Försti, Asta
author_sort Niazi, Yasmeen
collection PubMed
description 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.
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spelling pubmed-98183862023-01-07 Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma Niazi, Yasmeen Paramasivam, Nagarajan Blocka, Joanna Kumar, Abhishek Huhn, Stefanie Schlesner, Matthias Weinhold, Niels Sijmons, Rolf De Jong, Mirjam Durie, Brian Goldschmidt, Hartmut Hemminki, Kari Försti, Asta Cells Article 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. MDPI 2022-12-26 /pmc/articles/PMC9818386/ /pubmed/36611892 http://dx.doi.org/10.3390/cells12010096 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Niazi, Yasmeen
Paramasivam, Nagarajan
Blocka, Joanna
Kumar, Abhishek
Huhn, Stefanie
Schlesner, Matthias
Weinhold, Niels
Sijmons, Rolf
De Jong, Mirjam
Durie, Brian
Goldschmidt, Hartmut
Hemminki, Kari
Försti, Asta
Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma
title Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma
title_full Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma
title_fullStr Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma
title_full_unstemmed Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma
title_short Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma
title_sort investigation of rare non-coding variants in familial multiple myeloma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9818386/
https://www.ncbi.nlm.nih.gov/pubmed/36611892
http://dx.doi.org/10.3390/cells12010096
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