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oai:repisalud.isciii.es:20.500.12105/110752025-05-05T14:51:52Zcom_20.500.12105_2173com_20.500.12105_2051com_20.500.12105_15322com_20.500.12105_2052col_20.500.12105_19597col_20.500.12105_16968col_20.500.12105_19616

00925njm 22002777a 4500 dc Lin, Shu-Hong author Sampson, Joshua N author Grünewald, Thomas G P author Surdez, Didier author Reynaud, Stephanie author Mirabeau, Olivier author Karlins, Eric author Rubio, Rebeca Alba author Zaidi, Sakina author Grossetête-Lalami, Sandrine author Ballet, Stelly author Lapouble, Eve author Laurence, Valérie author Michon, Jean author Pierron, Gaelle author Kovar, Heinrich author Kontny, Udo author González-Neira, Anna author Alonso, Javier author Patiño-García, Ana author Corradini, Nadège author Bérard, Perrine Marec author Miller, Jeremy author Freedman, Neal D author Rothman, Nathaniel author Carter, Brian D author Dagnall, Casey L author Burdett, Laurie author Jones, Kristine author Manning, Michelle author Wyatt, Kathleen author Zhou, Weiyin author Yeager, Meredith author Cox, David G author Hoover, Robert N author Khan, Javed author Armstrong, Gregory T author Leisenring, Wendy M author Bhatia, Smita author Robison, Leslie L author Kulozik, Andreas E author Kriebel, Jennifer author Meitinger, Thomas author Metzler, Markus author Krumbholz, Manuela author Hartmann, Wolfgang author Strauch, Konstantin author Kirchner, Thomas author Dirksen, Uta author Mirabello, Lisa author Tirode, Franck author Tucker, Margaret A author Morton, Lindsay M author Chanock, Stephen J author Delattre, Olivier author Machiela, Mitchell J author 2020 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. PLoS One . 2020 Sep 3;15(9):e0237792. 10.1371/journal.pone.0237792 1932-6203 PloS one 32881892 http://hdl.handle.net/20.500.12105/11075 Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma