Open AccessLow-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma
Author(s) -
Shu-Hong Lin,
Joshua N. Sampson,
Thomas G. P. Grünewald,
Didier Surdez,
Stéphanie Reynaud,
Olivier Mirabeau,
Eric Karlins,
Rebeca Alba Rubío,
Sakina Zaïdi,
Sandrine Grossetête-Lalami,
Steven Ballet,
Eve Lapouble,
Valérie Laurence,
Jean Michon,
Gaëlle Pierron,
Heinrich Kovar,
Udo Kontny,
Anna GonzálezNeira,
Javier Alonso,
Ana PatiñoGarcía,
Nadège Corradini,
P Bérard,
Jeremy S. Miller,
Neal D. Freedman,
Nathaniel Rothman,
Brian D. Carter,
Casey 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 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
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0237792
Subject(s) - genome wide association study , germline , genetics , biology , locus (genetics) , haplotype , minor allele frequency , allele , genetic predisposition , allele frequency , genetic association , genetic variation , single nucleotide polymorphism , genotype , gene
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 < 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 ). 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.