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. 2020 Sep 3;15(9):e0237792.
doi: 10.1371/journal.pone.0237792. eCollection 2020.

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Shu-Hong Lin  1 , Joshua N Sampson  1 , Thomas G P Grünewald  2   3   4 , Didier Surdez  5 , Stephanie Reynaud  6 , Olivier Mirabeau  5   6 , Eric Karlins  1   7 , Rebeca Alba Rubio  2 , Sakina Zaidi  5   6 , Sandrine Grossetête-Lalami  5   6 , Stelly Ballet  6 , Eve Lapouble  6 , Valérie Laurence  6 , Jean Michon  6 , Gaelle Pierron  6 , Heinrich Kovar  8 , Udo Kontny  9 , Anna González-Neira  10 , Javier Alonso  11 , Ana Patino-Garcia  12 , Nadège Corradini  13 , Perrine Marec Bérard  13 , Jeremy Miller  14 , Neal D Freedman  1 , Nathaniel Rothman  1 , Brian D Carter  15 , Casey L Dagnall  1   7 , Laurie Burdett  1   7 , Kristine Jones  1   7 , Michelle Manning  1   7 , Kathleen Wyatt  1   7 , Weiyin Zhou  1   7 , Meredith Yeager  1   7 , David G Cox  16 , Robert N Hoover  1 , Javed Khan  17 , Gregory T Armstrong  18 , Wendy M Leisenring  19 , Smita Bhatia  20 , Leslie L Robison  18 , Andreas E Kulozik  21 , Jennifer Kriebel  22   23   24 , Thomas Meitinger  25   26 , Markus Metzler  27 , Manuela Krumbholz  27 , Wolfgang Hartmann  28 , Konstantin Strauch  29 , Thomas Kirchner  30 , Uta Dirksen  31   32 , Lisa Mirabello  1 , Margaret A Tucker  1 , Franck Tirode  5   6 , Lindsay M Morton  1 , Stephen J Chanock  1 , Olivier Delattre  5   6 , Mitchell J Machiela  1
Affiliations

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Shu-Hong Lin et al. PLoS One. .

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 < 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.

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Conflict of interest statement

The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Leidos Biomedical Research Inc. and Information Management Services, Inc. provided salaries for authors J.M., E.K., C.L.D., L.B., K.J., M.M., K.W., and W.Z. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Figures

Fig 1
Fig 1
Manhattan plots of analyses for all variants (A) and low-frequency and rare variants (MAF < 0.05) (B). Plotted p-values are for allelic tests by chromosome.
Fig 2
Fig 2. Patterns of Linkage Disequilibrium (LD) for rare, low-frequency and common variants associated with EwS at the chromosome 20p11.22–23 susceptibility locus.
R2 values are in shades of red while D’ values are in shades of blue, with darker values indicating higher degree of LD. All LD measures were estimated in LDlink using 1,000 Genomes Project European populations as the reference panel.
See this image and copyright information in PMC

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