Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism

Ni L. 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

doi:10.1016/j.celrep.2017.08.062

Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism

Ni L. 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 GoldschmidtKari Hemminki, Gareth J Morgan, Martin Kaiser, Richard S. Houlston

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	2556-2564
Number of pages	9
Journal	Cell Reports
Volume	20
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2017.08.062
Publication status	Published - 2017 Sept 12

Subject classification (UKÄ)

Cancer and Oncology
Medical Genetics

Free keywords

cancer genetics
genome-wide association studies
multiple myeloma
single nucleotide polymorphisms

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2017.08.062

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Li, N. L., Johnson, D. C., Weinhold, N., Kimber, S., Dobbins, S. E., Mitchell, J. S., Kinnersley, B., Sud, A., Law, P. J., Orlando, G., Scales, M., Wardell, C. P., Försti, A., Hoang, P. H., Went, M., Holroyd, A., Hariri, F., Pastinen, T., Meissner, T., ... Houlston, R. S. (2017). Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism. Cell Reports, 20(11), 2556-2564. https://doi.org/10.1016/j.celrep.2017.08.062

@article{bab8d70a7ca048b591507961e61ba8b3,

title = "Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism",

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 = "cancer genetics, genome-wide association studies, multiple myeloma, single nucleotide polymorphisms",

author = "Li, {Ni L.} and Johnson, {David C.} and Niels Weinhold and Scott Kimber and Dobbins, {Sara E.} and Mitchell, {Jonathan S} and Ben Kinnersley and Amit Sud and Law, {Philip J.} and Giulia Orlando and Matthew Scales and Wardell, {Christopher P.} and Asta F{\"o}rsti and Hoang, {Phuc H.} and Molly Went and Amy Holroyd and Fadi Hariri and Tomi Pastinen and Tobias Meissner and Hartmut Goldschmidt and Kari Hemminki and Morgan, {Gareth J} and Martin Kaiser and Houlston, {Richard S.}",

year = "2017",

month = sep,

day = "12",

doi = "10.1016/j.celrep.2017.08.062",

language = "English",

volume = "20",

pages = "2556--2564",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "11",

}

Li, NL, Johnson, DC, Weinhold, N, Kimber, S, Dobbins, SE, Mitchell, JS, Kinnersley, B, Sud, A, Law, PJ, Orlando, G, Scales, M, Wardell, CP, Försti, A, Hoang, PH, Went, M, Holroyd, A, Hariri, F, Pastinen, T, Meissner, T, Goldschmidt, H, Hemminki, K, Morgan, GJ, Kaiser, M & Houlston, RS 2017, 'Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism', Cell Reports, vol. 20, no. 11, pp. 2556-2564. https://doi.org/10.1016/j.celrep.2017.08.062

TY - JOUR

T1 - Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism

AU - Li, Ni L.

AU - Johnson, David C.

AU - Weinhold, Niels

AU - Kimber, Scott

AU - Dobbins, Sara E.

AU - Mitchell, Jonathan S

AU - Kinnersley, Ben

AU - Sud, Amit

AU - Law, Philip J.

AU - Orlando, Giulia

AU - Scales, Matthew

AU - Wardell, Christopher P.

AU - Försti, Asta

AU - Hoang, Phuc H.

AU - Went, Molly

AU - Holroyd, Amy

AU - Hariri, Fadi

AU - Pastinen, Tomi

AU - Meissner, Tobias

AU - Goldschmidt, Hartmut

AU - Hemminki, Kari

AU - Morgan, Gareth J

AU - Kaiser, Martin

AU - Houlston, Richard S.

PY - 2017/9/12

Y1 - 2017/9/12

N2 - 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.

AB - 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.

KW - cancer genetics

KW - genome-wide association studies

KW - multiple myeloma

KW - single nucleotide polymorphisms

U2 - 10.1016/j.celrep.2017.08.062

DO - 10.1016/j.celrep.2017.08.062

M3 - Article

C2 - 28903037

AN - SCOPUS:85029369362

SN - 2211-1247

VL - 20

SP - 2556

EP - 2564

JO - Cell Reports

JF - Cell Reports

IS - 11

ER -

Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism

Abstract

Subject classification (UKÄ)

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UN SDGs

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