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Search for rare protein altering variants influencing susceptibility to multiple myeloma

The genetic basis underlying the inherited risk of developing multiple myeloma (MM) is largely unknown. To examine the impact of rare protein altering variants on the risk of developing MM we analyzed high-coverage exome sequencing data on 513 MM cases and 1,569 healthy controls, performing both sin...

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Autores principales: Scales, Matthew, Chubb, Daniel, Dobbins, Sara E., Johnson, David C., Li, Ni, Sternberg, Michael J., Weinhold, Neils, Stein, Caleb, Jackson, Graham, Davies, Faith E., Walker, Brian A., Wardell, Christopher P., Houlston, Richard S., Morgan, Gareth J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482649/
https://www.ncbi.nlm.nih.gov/pubmed/28404951
http://dx.doi.org/10.18632/oncotarget.15874
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author Scales, Matthew
Chubb, Daniel
Dobbins, Sara E.
Johnson, David C.
Li, Ni
Sternberg, Michael J.
Weinhold, Neils
Stein, Caleb
Jackson, Graham
Davies, Faith E.
Walker, Brian A.
Wardell, Christopher P.
Houlston, Richard S.
Morgan, Gareth J.
author_facet Scales, Matthew
Chubb, Daniel
Dobbins, Sara E.
Johnson, David C.
Li, Ni
Sternberg, Michael J.
Weinhold, Neils
Stein, Caleb
Jackson, Graham
Davies, Faith E.
Walker, Brian A.
Wardell, Christopher P.
Houlston, Richard S.
Morgan, Gareth J.
author_sort Scales, Matthew
collection PubMed
description The genetic basis underlying the inherited risk of developing multiple myeloma (MM) is largely unknown. To examine the impact of rare protein altering variants on the risk of developing MM we analyzed high-coverage exome sequencing data on 513 MM cases and 1,569 healthy controls, performing both single variant and gene burden tests. We did not identify any recurrent coding low-frequency alleles (1–5%) with moderate effect that were statistically associated with MM. In a gene burden analysis we did however identify a promising relationship between variation in the marrow kinetochore microtubule stromal gene KIF18A, which plays a role in control mitotic chromosome positioning dynamics, and risk of MM (P =3.6×10(−6)). Further analysis showed KIF18A displays a distinct pattern of expression across molecular subgroups of MM as well as being associated with patient survival. Our results inform future study design and provide a resource for contextualizing the impact of candidate MM susceptibility genes.
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spelling pubmed-54826492017-06-27 Search for rare protein altering variants influencing susceptibility to multiple myeloma Scales, Matthew Chubb, Daniel Dobbins, Sara E. Johnson, David C. Li, Ni Sternberg, Michael J. Weinhold, Neils Stein, Caleb Jackson, Graham Davies, Faith E. Walker, Brian A. Wardell, Christopher P. Houlston, Richard S. Morgan, Gareth J. Oncotarget Research Paper The genetic basis underlying the inherited risk of developing multiple myeloma (MM) is largely unknown. To examine the impact of rare protein altering variants on the risk of developing MM we analyzed high-coverage exome sequencing data on 513 MM cases and 1,569 healthy controls, performing both single variant and gene burden tests. We did not identify any recurrent coding low-frequency alleles (1–5%) with moderate effect that were statistically associated with MM. In a gene burden analysis we did however identify a promising relationship between variation in the marrow kinetochore microtubule stromal gene KIF18A, which plays a role in control mitotic chromosome positioning dynamics, and risk of MM (P =3.6×10(−6)). Further analysis showed KIF18A displays a distinct pattern of expression across molecular subgroups of MM as well as being associated with patient survival. Our results inform future study design and provide a resource for contextualizing the impact of candidate MM susceptibility genes. Impact Journals LLC 2017-03-03 /pmc/articles/PMC5482649/ /pubmed/28404951 http://dx.doi.org/10.18632/oncotarget.15874 Text en Copyright: © 2017 Scales et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Scales, Matthew
Chubb, Daniel
Dobbins, Sara E.
Johnson, David C.
Li, Ni
Sternberg, Michael J.
Weinhold, Neils
Stein, Caleb
Jackson, Graham
Davies, Faith E.
Walker, Brian A.
Wardell, Christopher P.
Houlston, Richard S.
Morgan, Gareth J.
Search for rare protein altering variants influencing susceptibility to multiple myeloma
title Search for rare protein altering variants influencing susceptibility to multiple myeloma
title_full Search for rare protein altering variants influencing susceptibility to multiple myeloma
title_fullStr Search for rare protein altering variants influencing susceptibility to multiple myeloma
title_full_unstemmed Search for rare protein altering variants influencing susceptibility to multiple myeloma
title_short Search for rare protein altering variants influencing susceptibility to multiple myeloma
title_sort search for rare protein altering variants influencing susceptibility to multiple myeloma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482649/
https://www.ncbi.nlm.nih.gov/pubmed/28404951
http://dx.doi.org/10.18632/oncotarget.15874
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