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Lin, S.H.* ; Sampson, J.N.* ; Grünewald, T.G.P.* ; Surdez, D.* ; Reynaud, S.* ; Mirabeau, O.* ; Karlins, E.* ; Rubio, R.A.* ; Zaidi, S.* ; Grossetête-Lalami, S.* ; Ballet, S.* ; Lapouble, E.* ; Laurence, V.* ; Michon, J.* ; Pierron, G.* ; Kovar, H.* ; Kontny, U.* ; González-Neira, A.* ; Alonso, J.* ; Patino-Garcia, A.* ; Corradini, N.* ; Bérard, P.M.* ; Miller, J.* ; Freedman, N.D.* ; Rothman, N.* ; Carter, B.D.* ; Dagnall, C.L.* ; Burdett, L.* ; Jones, K.* ; Manning, M.* ; Wyatt, K.* ; Zhou, W.* ; Yeager, M.* ; Cox, D.G.* ; Hoover, R.N.* ; Khan, J.* ; Armstrong, G.T.* ; Leisenring, W.M.* ; Bhatia, S.* ; Robison, L.L.* ; Kulozik, A.E.* ; Kriebel, J. ; Meitinger, T. ; Metzler, M.* ; Krumbholz, M.* ; Hartmann, W.* ; Strauch, K.* ; Kirchner, T.* ; Dirksen, U.* ; Mirabello, L.* ; Tucker, M.A.* ; Tirode, F.* ; Morton, L.M.* ; Chanock, S.J.* ; Delattre, O.* ; Machiela, M.J.*

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

PLoS ONE 15:e0237792 (2020)

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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 < 5x10(-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 = 5.84x10(-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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Genomic Landscape; Cancer; Prostate; Design; Egr2

ISSN (print) / ISBN 1932-6203

Journal PLoS ONE

Quellenangaben Volume: 15, Issue: 9, Article Number: e0237792

Publisher Public Library of Science (PLoS)

Publishing Place Lawrence, Kan.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Epidemiology II (EPI2)
Institute of Human Genetics (IHG)

Grants National Cancer Institute
M la vie avec Lisa
Lulu et les petites bouilles de lune
les Amis de Claire
l'Etoile de Martin
Societe Francaise de lutte contre les Cancers et les leucemies de l'Enfant et de l'adolescent
Verein zur Forderung von Wissenschaft und Forschung an der Medizinischen Fakultat der LMU Munchen (WiFoMed)
LMU Munich's Institutional Strategy LMU excellent within the framework of the German Excellence Initiative
Mehr LEBEN fur krebskranke Kinder -Bettina-Bra u-Stiftung
Wilhelm Sander-Foundation
Barbara and Hubertus Trettner foundation
Gert and Susanna Mayer foundation
Enfants et Sante
Les Bagouzamanon
Intramural Research Program of the National Institutes of Health, National Cancer Institute
Intramural Research Program of the American Cancer Society
Institut Curie
Inserm
Ligue Nationale Contre le Cancer
Agence Nationale de la Recherche
European PROVABES
ASSET
FP7 grant "EURO EWING Consortium"
Courir pour Mathieu
Dans les pas du Geant
Matthias-Lackas foundation
Friedrich-Baur foundation
Dr. Leopold and Carmen Ellinger foundation
Asociacion Pablo Ugarte
Fundacion Sonrisa de Alex
ASION-La Hucha de Tomas
Sociedad Espanola de Hematologia y Oncologia Pediatricas
Cancer Center Support (CORE)
American Lebanese-Syrian Associated Charities (ALSAC)
Helmholtz Zentrum Munchen-German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
State of Bavaria
Munich Center of Health Sciences (MC-Health)
Ludwig-Maximilians-Universitat
Gobierno de Navarra, Proyectos de Biomedicina
Instituto de Salud Carlos III
Euro Ewing Consortium EEC under the European Commission Seventh Framework Program FP7-HEALTH
Dr. Rolf M. Schwiete foundation
Deutsche Forschungsgemeinschaft (DFG)
Barbara and Wilfried Mohr foundation
SMARCB1 e.V. assoication
German Cancer Aid
SiRIC
European Commission Seventh Framework Program FP7HEALTH "Euro Ewing Consortium EEC"
"Schornsteinfeger helfen krebskranken Kindern" Foundation
Trettner Foundation
ERA-Net-TRANSCAN consortium under the European Commission Seventh Framework Program FP7-HEALTH
Fundacion Caja Navarra/La Caixa