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

Lin SH, Sampson JN, Grünewald TG, Surdez D, Reynaud S, Mirabeau O, Karlins E, Rubio RA, 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 PM, Miller J, Freedman ND, Rothman N, Carter BD, Dagnall CL, Burdett L, Jones K, Manning M, Wyatt K, Zhou W, Yeager M, Cox DG, Hoover RN, Khan J, Armstrong GT, Leisenring WM, Bhatia S, Robison LL, Kulozik AE, Kriebel J, Meitinger T, Metzler M, Krumbholz M, Hartmann W, Strauch K, Kirchner T, Dirksen U, Mirabello L, Tucker MA, Tirode F, Morton LM, Chanock SJ, Delattre O, Machiela MJ (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Book Volume: 15

Article Number: e0237792

Journal Issue: 9 September

DOI: 10.1371/journal.pone.0237792

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.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Essen Germany (DE) Ludwig-Maximilians-Universität (LMU) Germany (DE) Ruprecht-Karls-Universität Heidelberg Germany (DE) National Cancer Institute (NCI) United States (USA) (US) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) Universitätsklinikum Münster Germany (DE) St. Jude Children’s Research Hospital United States (USA) (US) Fred Hutchinson Cancer Research Center United States (USA) (US) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) American Cancer Society United States (USA) (US) Institut Curie France (FR) Universitätsklinikum Aachen (UKA) Germany (DE) Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII) Spain (ES) Clínica Universidad de Navarra Spain (ES) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) University of Alabama at Birmingham (UAB) United States (USA) (US) St. Anna Kinderspital Austria (AT) Université de Lyon (UDL) France (FR) Information Management Services, Inc. (IMS) United States (USA) (US)

How to cite

APA:

Lin, S.H., Sampson, J.N., Grünewald, T.G., Surdez, D., Reynaud, S., Mirabeau, O.,... Machiela, M.J. (2020). Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma. PLoS ONE, 15(9 September). https://doi.org/10.1371/journal.pone.0237792

MLA:

Lin, Shu Hong, et al. "Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma." PLoS ONE 15.9 September (2020).

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