학술논문
Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.
Document Type
article
Author
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
Source
PLoS ONE, Vol 15, Iss 9, p e0237792 (2020)
Subject
Language
English
ISSN
1932-6203
Abstract
BackgroundEwing 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.MethodsWe 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).ResultsWe 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).ConclusionsThese findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.ImpactMotivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.