Scales, M., Chubb, D., Dobbins, S. E., Johnson, D. C., Li, N., Sternberg, M. J., Weinhold, N., Stein, C., Jackson, G., Davies, F. E., Walker, B. A., Wardell, C. P., Houlston, R. S., Morgan, G. J. (2017) Search for rare protein altering variants influencing susceptibility to multiple myeloma. Oncotarget, 8 (22). pp. 36203-36210. ISSN 1949-2553

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Abstract

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 = 3.6x10(-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.

Item Type:	Article
Authors (ICR Faculty only):	Houlston, Richard
All Authors:	Scales, M., Chubb, D., Dobbins, S. E., Johnson, D. C., Li, N., Sternberg, M. J., Weinhold, N., Stein, C., Jackson, G., Davies, F. E., Walker, B. A., Wardell, C. P., Houlston, R. S., Morgan, G. J.
Additional Information:	ISI Document Delivery No.: EX4UI Times Cited: 0 Cited Reference Count: 27 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. Myeloma UK; Bloodwise; Cancer Research UK (Bobby Moore Fund) [C1298/A8362]; Institute of Cancer Research Myeloma UK and Bloodwise provided principal funding. Additional funding was provided by Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund). M.S. was in receipt of a PhD studentship from The Institute of Cancer Research. 0 IMPACT JOURNALS LLC ORCHARD PARK ONCOTARGET
Uncontrolled Keywords:	multiple myeloma inherited risk exome sequencing GENOME-WIDE ASSOCIATION DNA-SEQUENCING DATA RISK PROLIFERATION EXPRESSION CARCINOMA FRAMEWORK
Research teams:	ICR divisions > Genetics and Epidemiology > Molecular & Population Genetics ICR divisions > Molecular Pathology > Molecular & Population Genetics ICR divisions > Molecular Pathology > Myeloma Group
Depositing User:	Barry Jenkins
Date Deposited:	07 Jul 2017 14:20
Last Modified:	07 Jul 2017 14:20
URI:	http://publications.icr.ac.uk/id/eprint/16072

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