Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.
oleh: Shu-Hong Lin, Joshua N Sampson, Thomas G P Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, Eric Karlins, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetête-Lalami, Stelly Ballet, Eve Lapouble, Valérie Laurence, Jean Michon, Gaelle Pierron, Heinrich Kovar, Udo Kontny, Anna González-Neira, Javier Alonso, Ana Patino-Garcia, Nadège Corradini, Perrine Marec Bérard, Jeremy Miller, Neal D Freedman, Nathaniel Rothman, Brian D Carter, Casey L Dagnall, Laurie Burdett, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G Cox, Robert N Hoover, Javed Khan, Gregory T Armstrong, Wendy M Leisenring, Smita Bhatia, Leslie L Robison, Andreas E Kulozik, Jennifer Kriebel, Thomas Meitinger, Markus Metzler, Manuela Krumbholz, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Uta Dirksen, Lisa Mirabello, Margaret A Tucker, Franck Tirode, Lindsay M Morton, Stephen J Chanock, Olivier Delattre, Mitchell J Machiela
| Format: | Article |
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| Diterbitkan: | Public Library of Science (PLoS) 2020-01-01 |
Deskripsi
<h4>Background</h4>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.<h4>Methods</h4>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).<h4>Results</h4>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).<h4>Conclusions</h4>These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.<h4>Impact</h4>Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.