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Ewing Sarcoma Risk Locus Analysis Sheds Light on Cancer's Formation

NEW YORK – An international team led by investigators in the US and France has characterized features found at a Ewing sarcoma risk locus on chromosome 6, uncovering germline microsatellite variants in the region that interact with a key somatic alteration in the condition: the presence of a GGAA motif-binding chimeric transcription factor known as EWSR1-FLI1.

"[O]ur findings describe the oncogenic interplay between a somatic driver mutation, EWSR1-FLI1, and a highly polymorphic GGAA microsatellite in the 6p25.1 [Ewing sarcoma genome-wide association study] susceptibility locus," the authors wrote.

As they reported in the American Journal of Human Genetics, the researchers, led by Mitchell Machiela of the National Cancer Institute and Olivier Delattre of INSERM and the Institut Curie, suspected that gene expression changes and related Ewing sarcoma-linked biological processes may stem from germline microsatellite variations at a risk locus known as 6p25.1. With the help of Pacific Biosciences' targeted long-read sequencing, they profiled 6p25.1 microsatellite alleles and EWSR1-FLI1 binding sites in blood samples from 385 individuals with or without Ewing sarcoma, a rare malignancy affecting bone or soft tissues.

The team's search flagged 50 microsatellite alleles within the Ewing sarcoma-linked chromosome 6p25.1 region and found that the 271 individuals with Ewing sarcoma were more likely to have longer microsatellites compared to the 114 unaffected controls. In addition, microsatellite alleles in the region were longer in individuals who carried a Ewing sarcoma risk variant in the region that was found in a prior genome-wide association study.

That shift appeared to coincide with the presence of slightly more of the germline GGAA motifs that are bound by the EWSR1-FLI1 transcription factor, a somatic Ewing sarcoma driver, the researchers reported. While individuals with Ewing sarcoma carried 19.2 GGAA motifs, on average, in microsatellite alleles from the 6p25.1 region, control participants had an average of almost 18.5 GGAA motifs.

By digging into variants in the region, they found a handful of SNPs on a shared haplotype that was linked to Ewing sarcoma risk, microsatellite lengths in the 6p25.1 region, and GGAA motif representation in the microsatellites.

In addition, results from the team's chromatin immunoprecipitation sequencing and gene knockdown experiments suggested that GGAA motif-rich microsatellites may have EWSR1-FLI1 enhancer activity in Ewing sarcoma cells, while boosting the expression of a RAS/MAP kinase transcription factor-coding gene called RREB1 in mesenchymal stem cells — an effect that appeared more closely tied to the GGAA motif than to AGAA or GGGA repeat motifs present in the microsatellite allele set.

"Longer GGAA repeats at 6p25.1 act as a de novo enhancer in the presence of EWSR1-FLI1 and confer an increase in [Ewing sarcoma] risk through enhanced binding affinity with EWSR1-FLI1 fusion protein and upregulation of RREB1," the authors explained, "which we observed to increase [Ewing sarcoma] cell proliferation and potentially DNA replication."

When the investigators knocked out the RREB1 gene in a Ewing sarcoma cell line, on the other hand, they saw a corresponding dip in cell proliferation, coupled with muted expression of genes related to cell cycle regulation or DNA replication in corresponding RNA sequencing experiments.

"Taken together, these observations suggest that regulation of RREB1 expression is mediated through the interaction between germline GGAA microsatellite variation and the somatic EWSR1-FLI fusion protein," the authors wrote.

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