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; Grossetete-Lalami, Sandrine; Ballet, Stelly; Lapouble, Eve; Laurence, Valerie; Michon, Jean; Pierron, Gaelle; Kovar, Heinrich; Kontny, Udo; Gonzalez-Neira, Anna; Alonso, Javier; Patino-Garcia, Ana; Corradini, Nadege; Berard, 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; Tucker, Margaret A.; Tirode, Franck; Morton, Lindsay M.; Chanock, Stephen J.; Delattre, Olivier und Machiela, Mitchell J. (2020): Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.
In: PLOS One 15(9), e0237792

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 < 5x10(-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 = 5.84x10(-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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1932-6203
• Sprache: Englisch