Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Mitchell J. Machiela; Thomas G.P. Grünewald; Didier Surdez; Stephanie Reynaud; Olivier Mirabeau; Eric Karlins; Rebeca Alba Rubio; Sakina Zaidi; Sandrine Grossetete-Lalami; Stelly Ballet; Eve Lapouble; Valérie Laurence; Jean Michon; Gaelle Pierron; Heinrich Kovar; Nathalie Gaspar; Udo Kontny; Anna González-Neira; Piero Picci; Javier Alonso; Ana Patino-Garcia; Nadège Corradini; Perrine Marec Bérard; Neal D. Freedman; Nathaniel Rothman; Casey L. Dagnall; Laurie Burdett; Kristine Jones; Michelle Manning; Kathleen Wyatt; Weiyin Zhou; Meredith Yeager; David G. Cox; Robert N. Hoover; Javed Khan; Gregory T. Armstrong; Wendy M. Leisenring; Smita Bhatia; Leslie L. Robison; Andreas E. Kulozik; Jennifer Kriebel; Thomas Meitinger; Markus Metzler; Wolfgang Hartmann; Konstantin Strauch; Thomas Kirchner; Uta Dirksen; Lindsay M. Morton; Lisa Mirabello; Margaret A. Tucker; Franck Tirode; Stephen J. Chanock; Olivier Delattre

doi:10.1038/s41467-018-05537-2

Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Mitchell J. Machiela
, Thomas G.P. Grünewald
, Didier Surdez
, Stephanie Reynaud
, Olivier Mirabeau
, Eric Karlins
, Rebeca Alba Rubio
, Sakina Zaidi
, Sandrine Grossetete-Lalami
, Stelly Ballet
, Eve Lapouble
, Valérie Laurence
, Jean Michon
, Gaelle Pierron
, Heinrich Kovar
, Nathalie Gaspar
, Udo Kontny
, Anna González-Neira
, Piero Picci
, Javier Alonso

Ana Patino-Garcia, Nadège Corradini, Perrine Marec Bérard, Neal D. Freedman, Nathaniel Rothman, Casey L. Dagnall, Laurie Burdett, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G. Cox, Robert N. Hoover, Javed Khan, Gregory T. Armstrong, Wendy M. Leisenring, Smita Bhatia, Leslie L. Robison, Andreas E. Kulozik, Jennifer Kriebel, Thomas Meitinger, Markus Metzler, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Uta Dirksen, Lindsay M. Morton, Lisa Mirabello, Margaret A. Tucker, Franck Tirode, Stephen J. Chanock, Olivier Delattre

Medicine and Health

National Cancer Institute (NCI)
University of Munich
German Consortium for Cancer Research (DKTK)
German Cancer Research Center
Institut Curie
Institut Curie
Centre Hospitalier, France
Inc.
University Children's Hospital
Gustave Roussy Cancer Campus
RWTH Aachen University
Spanish National Cancer Research Centre (CNIO)
IRCCS Istituto Ortopedico Rizzoli
Instituto de Investigación de Enfermedades Raras
Clínica Universitaria de Navarra
University of Lyon
Centre Léon Bérard
St. Jude Children's Research Hospital
Fred Hutchinson Cancer Research Center
Uni-versity of Alabama at Birmingham
University Hospital Heidelberg
Helmholtz Zentrum München German Research Center for Environmental Health
German Centre for Diabetes Research (DZD)
Universitätsklinikum Erlangen
Münster University Hospital
University Hospital of Essen

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

59 Scopus citations

Abstract

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

Original language	English
Article number	3184
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05537-2
State	Published - 1 Dec 2018

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10.1038/s41467-018-05537-2

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Machiela, M. J., Grünewald, T. G. P., Surdez, D., Reynaud, S., Mirabeau, O., Karlins, E., Rubio, R. A., Zaidi, S., Grossetete-Lalami, S., Ballet, S., Lapouble, E., Laurence, V., Michon, J., Pierron, G., Kovar, H., Gaspar, N., Kontny, U., González-Neira, A., Picci, P., ... Delattre, O. (2018). Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility. Nature Communications, 9(1), Article 3184. https://doi.org/10.1038/s41467-018-05537-2

@article{728e1e81a96143d6b876b1e8a1b388ba,

title = "Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility",

abstract = "Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.",

author = "Machiela, \{Mitchell J.\} and Gr{\"u}newald, \{Thomas G.P.\} and Didier Surdez and Stephanie Reynaud and Olivier Mirabeau and Eric Karlins and Rubio, \{Rebeca Alba\} and Sakina Zaidi and Sandrine Grossetete-Lalami and Stelly Ballet and Eve Lapouble and Val{\'e}rie Laurence and Jean Michon and Gaelle Pierron and Heinrich Kovar and Nathalie Gaspar and Udo Kontny and Anna Gonz{\'a}lez-Neira and Piero Picci and Javier Alonso and Ana Patino-Garcia and Nad{\`e}ge Corradini and B{\'e}rard, \{Perrine Marec\} and Freedman, \{Neal D.\} and Nathaniel Rothman and Dagnall, \{Casey L.\} and Laurie Burdett and Kristine Jones and Michelle Manning and Kathleen Wyatt and Weiyin Zhou and Meredith Yeager and Cox, \{David G.\} and Hoover, \{Robert N.\} and Javed Khan and Armstrong, \{Gregory T.\} and Leisenring, \{Wendy M.\} and Smita Bhatia and Robison, \{Leslie L.\} and Kulozik, \{Andreas E.\} and Jennifer Kriebel and Thomas Meitinger and Markus Metzler and Wolfgang Hartmann and Konstantin Strauch and Thomas Kirchner and Uta Dirksen and Morton, \{Lindsay M.\} and Lisa Mirabello and Tucker, \{Margaret A.\} and Franck Tirode and Chanock, \{Stephen J.\} and Olivier Delattre",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-05537-2",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Machiela, MJ, Grünewald, TGP, Surdez, D, Reynaud, S, Mirabeau, O, Karlins, E, Rubio, RA, Zaidi, S, Grossetete-Lalami, S, Ballet, S, Lapouble, E, Laurence, V, Michon, J, Pierron, G, Kovar, H, Gaspar, N, Kontny, U, González-Neira, A, Picci, P, Alonso, J, Patino-Garcia, A, Corradini, N, Bérard, PM, Freedman, ND, Rothman, N, Dagnall, CL, Burdett, L, Jones, K, Manning, M, Wyatt, K, Zhou, W, Yeager, M, Cox, DG, Hoover, RN, Khan, J, Armstrong, GT, Leisenring, WM, Bhatia, S, Robison, LL, Kulozik, AE, Kriebel, J, Meitinger, T, Metzler, M, Hartmann, W, Strauch, K, Kirchner, T, Dirksen, U, Morton, LM, Mirabello, L, Tucker, MA, Tirode, F, Chanock, SJ & Delattre, O 2018, 'Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility', Nature Communications, vol. 9, no. 1, 3184. https://doi.org/10.1038/s41467-018-05537-2

TY - JOUR

T1 - Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

AU - Machiela, Mitchell J.

AU - Grünewald, Thomas G.P.

AU - Surdez, Didier

AU - Reynaud, Stephanie

AU - Mirabeau, Olivier

AU - Karlins, Eric

AU - Rubio, Rebeca Alba

AU - Zaidi, Sakina

AU - Grossetete-Lalami, Sandrine

AU - Ballet, Stelly

AU - Lapouble, Eve

AU - Laurence, Valérie

AU - Michon, Jean

AU - Pierron, Gaelle

AU - Kovar, Heinrich

AU - Gaspar, Nathalie

AU - Kontny, Udo

AU - González-Neira, Anna

AU - Picci, Piero

AU - Alonso, Javier

AU - Patino-Garcia, Ana

AU - Corradini, Nadège

AU - Bérard, Perrine Marec

AU - Freedman, Neal D.

AU - Rothman, Nathaniel

AU - Dagnall, Casey L.

AU - Burdett, Laurie

AU - Jones, Kristine

AU - Manning, Michelle

AU - Wyatt, Kathleen

AU - Zhou, Weiyin

AU - Yeager, Meredith

AU - Cox, David G.

AU - Hoover, Robert N.

AU - Khan, Javed

AU - Armstrong, Gregory T.

AU - Leisenring, Wendy M.

AU - Bhatia, Smita

AU - Robison, Leslie L.

AU - Kulozik, Andreas E.

AU - Kriebel, Jennifer

AU - Meitinger, Thomas

AU - Metzler, Markus

AU - Hartmann, Wolfgang

AU - Strauch, Konstantin

AU - Kirchner, Thomas

AU - Dirksen, Uta

AU - Morton, Lindsay M.

AU - Mirabello, Lisa

AU - Tucker, Margaret A.

AU - Tirode, Franck

AU - Chanock, Stephen J.

AU - Delattre, Olivier

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

AB - Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

UR - https://www.scopus.com/pages/publications/85051514728

U2 - 10.1038/s41467-018-05537-2

DO - 10.1038/s41467-018-05537-2

M3 - Article

C2 - 30093639

AN - SCOPUS:85051514728

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3184

ER -

Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Abstract

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