Journal articles

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, *}

* Corresponding author

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 University Children's Hospital of Heidelberg [Heidelberg, Germany]

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 [Essen, Germany]

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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Cancer

Life Sciences [q-bio] / Biochemistry, Molecular Biology / Genomics [q-bio.GN]

Life Sciences [q-bio] / Biochemistry, Molecular Biology / Molecular biology

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