Cell Reports (Sep 2017)
Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism
- Ni Li,
- David C. Johnson,
- Niels Weinhold,
- Scott Kimber,
- Sara E. Dobbins,
- Jonathan S. Mitchell,
- Ben Kinnersley,
- Amit Sud,
- Philip J. Law,
- Giulia Orlando,
- Matthew Scales,
- Christopher P. Wardell,
- Asta Försti,
- Phuc H. Hoang,
- Molly Went,
- Amy Holroyd,
- Fadi Hariri,
- Tomi Pastinen,
- Tobias Meissner,
- Hartmut Goldschmidt,
- Kari Hemminki,
- Gareth J. Morgan,
- Martin Kaiser,
- Richard S. Houlston
Affiliations
- Ni Li
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- David C. Johnson
- Division of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Niels Weinhold
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AK 72205, USA
- Scott Kimber
- Division of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Sara E. Dobbins
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Jonathan S. Mitchell
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Ben Kinnersley
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Amit Sud
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Philip J. Law
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Giulia Orlando
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Matthew Scales
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Christopher P. Wardell
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AK 72205, USA
- Asta Försti
- German Cancer Research Center, 69120 Heidelberg, Germany
- Phuc H. Hoang
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Molly Went
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Amy Holroyd
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Fadi Hariri
- McGill University and Genome Quebec Innovation Centre, Department of Human Genetics, McGill University, Montreal, Quebec, QC H3A 0G1, Canada
- Tomi Pastinen
- McGill University and Genome Quebec Innovation Centre, Department of Human Genetics, McGill University, Montreal, Quebec, QC H3A 0G1, Canada
- Tobias Meissner
- Department of Molecular and Experimental Medicine, Avera Cancer Institute, La Jolla, CA 92037, USA
- Hartmut Goldschmidt
- Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany
- Kari Hemminki
- German Cancer Research Center, 69120 Heidelberg, Germany
- Gareth J. Morgan
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AK 72205, USA
- Martin Kaiser
- Division of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- Richard S. Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK
- DOI
- https://doi.org/10.1016/j.celrep.2017.08.062
- Journal volume & issue
-
Vol. 20,
no. 11
pp. 2556 – 2564
Abstract
Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.
Keywords