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 AlonsoAna 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 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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 languageEnglish (US)
Article number3184
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Ewing's Sarcoma
genome
Genome-Wide Association Study
loci
Genes
cancer
magnetic permeability
Fusion reactions
Pediatrics
Neoplasms
genes
Quantitative Trait Loci
Genetic Association Studies
fusion
Single Nucleotide Polymorphism
Odds Ratio
Proteins
proteins
estimates

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Machiela, M. J., Grünewald, T. G. P., Surdez, D., Reynaud, S., Mirabeau, O., Karlins, E., ... Delattre, O. (2018). Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility. Nature communications, 9(1), [3184]. https://doi.org/10.1038/s41467-018-05537-2

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

In: Nature communications, Vol. 9, No. 1, 3184, 01.12.2018.

Research output: Contribution to journalArticle

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, G, 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
Machiela, Mitchell J. ; Grünewald, Thomas G.P. ; Surdez, Didier ; Reynaud, Stephanie ; Mirabeau, Olivier ; Karlins, Eric ; Rubio, Rebeca Alba ; Zaidi, Sakina ; Grossetete-Lalami, Sandrine ; Ballet, Stelly ; Lapouble, Eve ; Laurence, Valérie ; Michon, Jean ; Pierron, Gaelle ; Kovar, Heinrich ; Gaspar, Nathalie ; Kontny, Udo ; González-Neira, Anna ; Picci, Piero ; Alonso, Javier ; Patino-Garcia, Ana ; Corradini, Nadège ; Bérard, Perrine Marec ; Freedman, Neal D. ; Rothman, Nathaniel ; Dagnall, Casey L. ; Burdett, Laurie ; Jones, Kristine ; Manning, Michelle ; Wyatt, Kathleen ; Zhou, Weiyin ; Yeager, Meredith ; Cox, David G. ; Hoover, Robert N. ; Khan, Javed ; Armstrong, Gregory ; Leisenring, Wendy M. ; Bhatia, Smita ; Robison, Leslie L. ; Kulozik, Andreas E. ; Kriebel, Jennifer ; Meitinger, Thomas ; Metzler, Markus ; Hartmann, Wolfgang ; Strauch, Konstantin ; Kirchner, Thomas ; Dirksen, Uta ; Morton, Lindsay M. ; Mirabello, Lisa ; Tucker, Margaret A. ; Tirode, Franck ; Chanock, Stephen J. ; Delattre, Olivier. / Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility. In: Nature communications. 2018 ; Vol. 9, No. 1.
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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.",
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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

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

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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.

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