Browsing by Author "Dagnall, Casey L"
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Publication Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility(Nature Publishing Group, 2018) 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 T; 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; Unión EuropeaEwing 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.Publication Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.(Public Library of Science (PLOS), 2020) Lin, Shu-Hong; Sampson, Joshua N; Grünewald, Thomas G P; Surdez, Didier; Reynaud, Stephanie; Mirabeau, Olivier; Karlins, Eric; Rubio, Rebeca Alba; Zaidi, Sakina; Grossetête-Lalami, Sandrine; Ballet, Stelly; Lapouble, Eve; Laurence, Valérie; Michon, Jean; Pierron, Gaelle; Kovar, Heinrich; Kontny, Udo; González-Neira, Anna; Alonso, Javier; Patino-Garcia, Ana; Corradini, Nadège; Bérard, Perrine Marec; Miller, Jeremy; Freedman, Neal D; Rothman, Nathaniel; Carter, Brian D; 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 T; Leisenring, Wendy M; Bhatia, Smita; Robison, Leslie L; Kulozik, Andreas E; Kriebel, Jennifer; Meitinger, Thomas; Metzler, Markus; Krumbholz, Manuela; Hartmann, Wolfgang; Strauch, Konstantin; Kirchner, Thomas; Dirksen, Uta; Mirabello, Lisa; Tirode, Franck; Tucker, Margaret A; Morton, Lindsay M; Chanock, Stephen J; Delattre, Olivier; Machiela, Mitchell J; NIH - National Cancer Institute (NCI) (Estados Unidos); Agence Nationale de la Recherche (Francia); Unión Europea. Comisión Europea. 7 Programa Marco; Deutsche Forschungsgemeinschaft (Alemania); Instituto de Salud Carlos III; Comunidad Foral de Navarra (España)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. 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). 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). These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.