Work

Search for rare protein altering variants influencing susceptibility to multiple myeloma

Year: 2017

Type: article

Abstract: // Matthew Scales 1, 2 , Daniel Chubb 1 , Sara E. Dobbins 1 , David C. Johnson 1, 3 , Ni Li 1 , Michael J. Sternberg 2 , Neils Weinhold 4 , Caleb Stein 4 , Graham Jackson 5 , Faith E. Davies 4 , Brian A. Walker 4 , Christopher P. Wardell 4 , Richard S. Houlston 1, 3 and Gareth J. Morgan 4 1 Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK 2 Centre of Bioinformatics and Systems Biology, Department of Life Sciences, Imperial College London, London, UK 3 Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey, UK 4 The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA 5 Department of Haematology, Newcastle University, Newcastle, UK Correspondence to: Richard S. Houlston, email: [email protected] Keywords: multiple myeloma, inherited risk, exome sequencing Received: September 30, 2016 Accepted: January 28, 2017 Published: March 03, 2017 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.15874