Dataset Information

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

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.

SUBMITTER: Lin SH

PROVIDER: S-EPMC7470401 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

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

Lin Shu-Hong SH Sampson Joshua N JN Grünewald Thomas G P TGP Surdez Didier D Reynaud Stephanie S Mirabeau Olivier O Karlins Eric E Rubio Rebeca Alba RA Zaidi Sakina S Grossetête-Lalami Sandrine S Ballet Stelly S Lapouble Eve E Laurence Valérie V Michon Jean J Pierron Gaelle G Kovar Heinrich H Kontny Udo U González-Neira Anna A Alonso Javier J Patino-Garcia Ana A Corradini Nadège N Bérard Perrine Marec PM Miller Jeremy J Freedman Neal D ND Rothman Nathaniel N Carter Brian D BD Dagnall Casey L CL Burdett Laurie L Jones Kristine K Manning Michelle M Wyatt Kathleen K Zhou Weiyin W Yeager Meredith M Cox David G DG Hoover Robert N RN Khan Javed J Armstrong Gregory T GT Leisenring Wendy M WM Bhatia Smita S Robison Leslie L LL Kulozik Andreas E AE Kriebel Jennifer J Meitinger Thomas T Metzler Markus M Krumbholz Manuela M Hartmann Wolfgang W Strauch Konstantin K Kirchner Thomas T Dirksen Uta U Mirabello Lisa L Tucker Margaret A MA Tirode Franck F Morton Lindsay M LM Chanock Stephen J SJ Delattre Olivier O Machiela Mitchell J MJ

PloS one 20200903 9

<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 contrib ...[more]

PMID: 32881892

Similar Datasets

Project description:Adamantinoma-like Ewing sarcoma (ALES) has traditionally been considered a variant of Ewing sarcoma because it generally harbors EWSR1::FLI1 fusions despite showing diffuse positivity for keratins and p40. However, it has become increasingly recognized that different tumors can have identical translocations, including shared fusions between carcinomas and sarcomas, raising questions as to whether ALES might represent a separate entity. Using methylation profiling, we further explored the relationship between Ewing sarcoma and ALES. The archives of multiple institutions were searched for candidate cases of ALES. DNA methylation profiling was performed and results were compared to corresponding data from conventional Ewing sarcoma. Twelve cases of ALES (5 previously reported) were identified in 10 men and 2 women (aged 20-72 years; median age, 41.5 years). Cases included tumors arising in the parotid gland (3), sinonasal cavity (2), submandibular gland (2), thyroid gland (1), neck (1), gingiva (1), hypopharynx (1), and mandible (1). Histologic review consistently showed sheets and nests of basaloid cells within a fibromyxoid or hyalinized stroma. All tumors were positive for at least 1 keratin and CD99 expression, whereas all 10 cases tested were positive for p63 or p40; S100 protein expression was noted in 2 cases. Cases harbored either EWSR1::FLI1 fusions (n = 6), FUS::FLI1 fusions (n = 1), and/or EWSR1 rearrangements (n = 6). Methylation profiling was successful in 11/12 cases evaluated. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) of DNA methylation data revealed a distinct methylation cluster for all 11 cases, including the tumor with the FUS::FLI1 fusion, which clearly segregated them from the conventional Ewing sarcoma. Follow-up (n = 11, 1-154 months) revealed that 4 patients experienced recurrence and 6 developed metastatic disease. ALES demonstrates a distinct methylation signature from conventional Ewing sarcoma. This finding adds to the distinctive immunoprofile of ALES, suggesting that these 2 tumors should be considered distinct entities rather than histologic extremes of the same disease.

Dataset Information

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

Background

Methods

Results

Conclusions

Impact

Publications

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

Similar Datasets

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