Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/11075
Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.
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 CNIO | Alonso, Javier ISCIII | 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
PLoS One . 2020 Sep 3;15(9):e0237792.
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.
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