Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

PLoS One. 2020 Sep 3;15(9):e0237792. doi: 10.1371/journal.pone.0237792. eCollection 2020.

Abstract

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.

Methods: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).

Results: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8).

Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.

Impact: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genome-Wide Association Study
  • Germ Cells / metabolism*
  • Humans
  • Linkage Disequilibrium / genetics
  • Odds Ratio
  • Polymorphism, Single Nucleotide / genetics
  • Sarcoma, Ewing / genetics*

Grant support

This work was supported by the National Cancer Institute (CA55727, G.T. Armstrong, Principal Investigator), with additional funding for genotyping from the Intramural Research Program of the National Institutes of Health, National Cancer Institute and the Intramural Research Program of the American Cancer Society. This work was supported by grants from the Institut Curie, the Inserm, the Ligue Nationale Contre le Cancer (Equipe labellisée, Carte d’Identité des Tumeurs program and Recherche Epidémiologique 2009 program), the ANR-10-EQPX-03 from the Agence Nationale de la Recherche, the European PROVABES (ERA-649 NET TRANSCAN JTC-2011), and ASSET (FP7-HEALTH-2010-259348) projects. This research was supported by FP7 grant “EURO EWING Consortium” No. 602856 and the following associations: Courir pour Mathieu, Dans les pas du Géant, Les Bagouzamanon, Enfants et Santé, M la vie avec Lisa, Lulu et les petites bouilles de lune, les Amis de Claire, l’Etoile de Martin and the Société Française de lutte contre les Cancers et les leucémies de l’Enfant et de l’adolescent. The laboratory of T. G. P. Grünewald is supported by grants from the ‘Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der LMU München (WiFoMed)’, by LMU Munich’s Institutional Strategy LMU excellent within the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Wilhelm Sander-Foundation (2016.167.1), the Barbara and Hubertus Trettner foundation, the Gert and Susanna Mayer foundation, the Matthias-Lackas foundation, the Friedrich-Baur foundation, the Dr. Leopold and Carmen Ellinger foundation, the Dr. Rolf M. Schwiete foundation, the Deutsche Forschungsgemeinschaft (DFG 391665916), the Barbara and Wilfried Mohr foundation, the SMARCB1 e.V. assoication, and by the German Cancer Aid (DKH-70112257). D. Surdez is supported by SiRIC (Grant « INCa-DGOS-4654). The Metzler lab received grants from the European Commission Seventh Framework Program FP7-HEALTH “Euro Ewing Consortium EEC”, project number EU-FP7 602856, the “Schornsteinfeger helfen krebskranken Kindern” Foundation and the Trettner Foundation. The group of U. Dirksen is supported by the German Cancer Aid grant 108128, the Barbara and Hubertus Trettner foundation, the Gert and Susanna Mayer foundation; ERA-Net-TRANSCAN consortium ´PROVABES´ (01KT1310), and Euro Ewing Consortium EEC, project number EU-FP7 602856, both funded under the European Commission Seventh Framework Program FP7-HEALTH (http://cordis.europa.eu/); This work was supported by the Instituto de Salud Carlos III (PI16CIII/00026) and the Asociación Pablo Ugarte, Fundación Sonrisa de Alex, ASION-La Hucha de Tomás, Sociedad Española de Hematología y Oncología Pediátricas. Support to St. Jude Children’s Research Hospital also provided by the Cancer Center Support (CORE) grant (CA21765, C. Roberts, Principal Investigator) and the American Lebanese-Syrian Associated Charities (ALSAC). The KORA study was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The laboratory of A.P. Garcia is supported by Gobierno de Navarra, Proyectos de Biomedicina 2018. Ref. 54/2018 and Fundación Caja Navarra/La Caixa to Niños Contra el Cáncer. Leidos Biomedical Research Inc. and Information Management Services, Inc. provided support in the form of salaries for authors J.M., E.K., C.L.D., L.B., K.J., M.M., K.W., W.Z., and M.Y., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.