Key result
The low-frequency variant rs112837127 on chromosome 20 was independently associated with a reduced risk of Ewing sarcoma (OR 0.20).
Why the study?
Genome-wide association studies had identified 6 common germline susceptibility loci for Ewing sarcoma, but low-frequency inherited variants with minor allele frequencies below 5% had not been investigated due to limited genotyped cases.
Do low-frequency germline variants alter the risk of Ewing sarcoma in individuals of European ancestry?
Case-Control (n=2,079)
Yes
Do low-frequency germline variants alter the risk of Ewing sarcoma in individuals of European ancestry?
Odds Ratio: 0.2 (95% CI 0.09–0.4)
p-value: p=5.84x10^-8
Low-frequency germline variants, such as rs112837127, independently contribute to Ewing sarcoma susceptibility, highlighting the complex genetic architecture of this rare tumor.
This is the authors' abstract. We don't add key points for this paper.
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.
Supports low-frequency variant role in Ewing sarcoma susceptibility; leaves open clinical utility of rs112837127 testing pending validation.
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Lin et al. (2020) conducted a case-control in Ewing sarcoma (n=2,079). Low-frequency variant rs112837127 vs. Absence of variant (major allele) was evaluated on Risk of Ewing sarcoma (OR 0.20, 95% CI 0.09-0.40, p=5.84x10^-8). The low-frequency variant rs112837127 on chromosome 20 was independently associated with a reduced risk of Ewing sarcoma (OR 0.20).
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