Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility
Mitchell J Machiela
(1)
,
Thomas G P Grünewald
(2, 3, 4)
,
Stéphanie Reynaud
(5)
,
Didier Surdez
(6, 7)
,
Olivier Mirabeau
(6, 7)
,
Eric Karlins
(1, 8)
,
Rebeca Alba Rubio
(2)
,
Sakina Zaïdi
(6, 7)
,
Sandrine Grossetete-Lalami
(6, 7)
,
Stelly Ballet
(7, 9)
,
Eve Lapouble
(7, 9)
,
Valérie Laurence
(7)
,
Jean Michon
(7)
,
Gaëlle Pierron
(7, 9)
,
Heinrich Kovar
(10)
,
Nathalie Gaspar
(11)
,
Udo Kontny
(12)
,
Anna González-Neira
(13)
,
Piero Picci
(14)
,
Javier Alonso
(15)
,
Ana Patiño-García
(16)
,
Nadège Corradini
(17)
,
Perrine Marec Bérard
(17)
,
Neal Freedman
(1)
,
Nathaniel Rothman
(1)
,
Casey Dagnall
(1, 8)
,
Laurie Burdett
(1, 8)
,
Kristine Jones
(1, 8)
,
Michelle Manning
(1, 8)
,
Kathleen Wyatt
(1, 8)
,
Weiyin Zhou
(1, 8)
,
Meredith Yeager
(1, 8)
,
David Cox
(18)
,
Robert Hoover
(1)
,
Javed Khan
(19)
,
Gregory Armstrong
(20)
,
Wendy Leisenring
(21)
,
Smita Bhatia
(22)
,
Leslie Robison
(20)
,
Andreas Kulozik
(23)
,
Jennifer Kriebel
(24, 25, 26)
,
Thomas Meitinger
(27, 28)
,
Markus Metzler
(29)
,
Wolfgang Hartmann
(30)
,
Konstantin Strauch
(31, 32)
,
Thomas Kirchner
(3, 4, 33)
,
Uta Dirksen
(34)
,
Lindsay M. Morton
(1)
,
Lisa Mirabello
(1)
,
Margaret Tucker
(1)
,
Franck Tirode
(6, 7)
,
Stephen Chanock
(1)
,
Olivier Delattre
(6, 7)
1
Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics
2 Laboratory for Pediatric Sarcoma Biology [Munich, Germany]
3 DKTK - German Cancer Consortium [Heidelberg]
4 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
5 Unité de Génétique Somatique
6 U830 - Unité de génétique et biologie des cancers
7 Département d'Oncologie Médicale [Institut Curie, Paris]
8 Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics
9 Unité de Génétique Somatique [Institut Curie, Paris]
10 Children’s Cancer Research Institute [Vienna, Austria]
11 Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy]
12 Division of Pediatric Hematology, Oncology and Stem Cell Transplantation [Aechen, Germany]
13 Genotyping Unit (CeGen), Human Cancer Genetics Programme
14 Istituto Ortopedico Rizzoli [Bologna, Italy]
15 Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain]
16 CIMA - Center for Applied Medical Research [Plamplona]
17 IHOPe - Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL]
18 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
19 Clinical Genetics Branch
20 Department of Epidemiology and Cancer Control [Memphis, TN, USA]
21 Cancer Prevention and Clinical Statistics Program [Seattle, WA, USA]
22 Institute for Cancer Outcomes and Survivorship [Birmingham, AL, USA]
23 Heidelberg University Hospital [Heidelberg]
24 Research Unit of Molecular Biology [Neuherberg, Germany]
25 EPI - Institute of Epidemiology [Neuherberg]
26 DZD - German Center for Diabetes Diseases [Neuherberg, Germany]
27 IHG - Institute of Human Genetics [Neuherberg]
28 Institute of Human Genetics [Munich, Germany]
29 Pediatric Oncology and Hematology [Erlangen, Germany]
30 Gerhard-Domagk-Institute of Pathology
31 Institute of Genetic Epidemiology [Neuherberg, Germany]
32 IBE - Chair of Genetic Epidemiology [Munich, Germany]
33 Institute of Pathology [Munich, Germany]
34 University Children's Hospital of Essen
2 Laboratory for Pediatric Sarcoma Biology [Munich, Germany]
3 DKTK - German Cancer Consortium [Heidelberg]
4 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
5 Unité de Génétique Somatique
6 U830 - Unité de génétique et biologie des cancers
7 Département d'Oncologie Médicale [Institut Curie, Paris]
8 Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics
9 Unité de Génétique Somatique [Institut Curie, Paris]
10 Children’s Cancer Research Institute [Vienna, Austria]
11 Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy]
12 Division of Pediatric Hematology, Oncology and Stem Cell Transplantation [Aechen, Germany]
13 Genotyping Unit (CeGen), Human Cancer Genetics Programme
14 Istituto Ortopedico Rizzoli [Bologna, Italy]
15 Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain]
16 CIMA - Center for Applied Medical Research [Plamplona]
17 IHOPe - Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL]
18 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
19 Clinical Genetics Branch
20 Department of Epidemiology and Cancer Control [Memphis, TN, USA]
21 Cancer Prevention and Clinical Statistics Program [Seattle, WA, USA]
22 Institute for Cancer Outcomes and Survivorship [Birmingham, AL, USA]
23 Heidelberg University Hospital [Heidelberg]
24 Research Unit of Molecular Biology [Neuherberg, Germany]
25 EPI - Institute of Epidemiology [Neuherberg]
26 DZD - German Center for Diabetes Diseases [Neuherberg, Germany]
27 IHG - Institute of Human Genetics [Neuherberg]
28 Institute of Human Genetics [Munich, Germany]
29 Pediatric Oncology and Hematology [Erlangen, Germany]
30 Gerhard-Domagk-Institute of Pathology
31 Institute of Genetic Epidemiology [Neuherberg, Germany]
32 IBE - Chair of Genetic Epidemiology [Munich, Germany]
33 Institute of Pathology [Munich, Germany]
34 University Children's Hospital of Essen
Didier Surdez
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- PersonId : 786620
- ORCID : 0000-0002-7118-7859
- IdRef : 238471330
Olivier Mirabeau
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- IdHAL : olivier-mirabeau
- ORCID : 0000-0002-4048-1385
Heinrich Kovar
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Nathalie Gaspar
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- PersonId : 1025224
Javier Alonso
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- PersonId : 897614
Nathaniel Rothman
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Robert Hoover
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- PersonId : 908786
Franck Tirode
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- IdHAL : franck-tirode
- ORCID : 0000-0003-4731-7817
- IdRef : 161841147
Stephen Chanock
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Olivier Delattre
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- ORCID : 0000-0002-8730-2276
- IdRef : 07462766X
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Résumé
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.
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