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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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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

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Project description:RationaleEwing-like sarcoma (ELS)/undifferentiated round cell sarcoma (URCS) is a rare type of soft tissue sarcomas (STS), especially in infants, with poor prognosis. It is a so-called "small round cell" sarcoma, and has many features of Ewing sarcoma, but lacks rearrangements in EWSR1. The diagnosis and treatment of this kind of STS remains challenging. BCOR genetic abnormalities have been found in some Ewing-like sarcomas.Patient concernsThis report presents an ELS case of a female infant, who was 2 months old when initially diagnosed, with the clinical stage of IIIA (G2T2N0M0). Histologic findings revealed an undifferentiated neoplasm composed of small round tumor cells with round, open chromatic nuclei, and scant cytoplasm in a sheet growth pattern. Fluorescence in situ hybridization (FISH) analysis showed absence of EWSR1 and ETV6 gene rearrangement. Molecular genetic testing found no established variants of clinical significance but variants of unknown significance in APC, KMT2D, and MSH6 were detected. Immunostaining revealed that the tumor cells were positive for TLE1 and BCOR, and negative for cytokeratin (AE1/AE3), Desmin, CD45, S100, CD31, HMB45, and SATB2. INI-1 was retained.DiagnosisEwing-like sarcoma (ELS)/undifferentiated round cell sarcoma (URCS) INTERVENTIONS:: After initial diagnosis, the patient received 4 cycles of combination chemotherapy for 2 months. Radical amputation of left upper extremity was performed 3 months after diagnosis. Postoperative chemotherapy was continued for 6 cycles.OutcomesThe patient died of intracranial metastasis with hemorrhage in 13 months after initial diagnosis, 5 months after the last cycle of chemotherapy.LessonsELS in infancy is extremely rare and has a poorer prognosis than Ewing sarcoma or infantile fibrosarcoma. APC and MSH6 variation might be related with the disease progression and predict a poorer prognosis. This rare case promotes better understanding of the disease and suggests a promising role for the combination chemotherapy regimen in treating infantile ELS. Importantly, it brings to light the possibility of intracranial metastasis, which requires proactive screening for timely detection.

Dataset Information

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

Publications

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

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