title: Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma.
abstract: Survival following a diagnosis of multiple myeloma (MM) varies between patients and some of these differences may be a consequence of inherited genetic variation. In this study, to identify genetic markers associated with MM overall survival (MM-OS), we conduct a meta-analysis of four patient series of European ancestry, totalling 3,256 patients with 1,200 MM-associated deaths. Each series is genotyped for ∼600,000 single nucleotide polymorphisms across the genome; genotypes for six million common variants are imputed using 1000 Genomes Project and UK10K as the reference. The association between genotype and OS is assessed by Cox proportional hazards model adjusting for age, sex, International staging system and treatment. We identify a locus at 6q25.1 marked by rs12374648 associated with MM-OS (hazard ratio=1.34, 95% confidence interval=1.22-1.48, P=4.69 × 10(-9)). Our findings have potential clinical implications since they demonstrate that inherited genotypes can provide prognostic information in addition to conventional tumor acquired prognostic factors.
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: David C
authors.identifier: http://orcid.org/0000-0003-0887-3343
authors.initials: DC
authors.lastname: Johnson
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.|Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Mitchell
authors.affiliation: German Cancer Research Center, 69121 Heidelberg, Germany.
authors.forename: Bowang
authors.initials: B
authors.lastname: Chen
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Dil B
authors.initials: DB
authors.lastname: Begum
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Hillengass
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Bertsch
authors.affiliation: Leeds Institute of Molecular Medicine, Section of Clinical Trials Research, University of Leeds, Leeds LS2 9PH, UK.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Gregory
authors.affiliation: Leeds Institute of Molecular Medicine, Section of Clinical Trials Research, University of Leeds, Leeds LS2 9PH, UK.
authors.forename: David
authors.identifier: http://orcid.org/0000-0002-2338-0179
authors.initials: D
authors.lastname: Cairns
authors.affiliation: Department of Haematology, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK.
authors.forename: Graham H
authors.initials: GH
authors.lastname: Jackson
authors.affiliation: German Cancer Research Center, 69121 Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, 221 00 Malmö, Sweden.
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Nickel
authors.affiliation: Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.|Division of Medical Genetics, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.|Department of Genomics, Life &Brain Center, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöethen
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Owen W
authors.initials: OW
authors.lastname: Stephens
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davis
authors.affiliation: German Cancer Research Center, 69121 Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, 221 00 Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.|National Center of Tumor Diseases, 69120 Heidelberg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SW7 3RP, UK.|Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D000368:Aged; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D044465:White People / Q000235:genetics