A pediatric bone cancer defined by an acquired gene fusion — and one of this page's three inherited risk variants sits directly beside a gene that same fusion protein switches on.
Ewing sarcoma is a pediatric tumor of bone and soft tissue, defined by an acquired EWSR1-ETS gene fusion and occurring predominantly in people of European ancestry. This page holds 3 inherited (germline) variants from the study that first mapped its genetic risk.
A 2012 study genotyped 401 French cases against 684 French and 3,668 US-based controls of European descent, then replicated its findings in two further independent case-control sets. The joint analysis confirmed three loci: rs9430161, 25kb upstream of TARDBP; rs224278, 5kb upstream of EGR2; and, with a weaker signal, rs4924410 at 15q15.
The paper draws two specific connections rather than leaving these as bare statistics. TARDBP shares structural similarity with EWSR1 and FUS — both genes for RNA-binding proteins, and EWSR1 is itself one half of the acquired EWSR1-ETS fusion that actually drives the cancer. And EGR2 is a direct target gene of that same fusion protein — meaning an inherited variant near EGR2 sits beside a gene the tumor's own acquired driver mutation switches on once the disease develops. The study confirmed all three loci affect real gene expression levels (of TARDBP, ADO and EGR2), not just disease risk statistically.
The study also found the major risk haplotypes at these loci were less common in people of African ancestry — offering a possible genetic explanation for Ewing sarcoma's already-known lower incidence in that population, rather than leaving it unexplained.
Positions joined since this page was written
What this is The text above discusses the variants this page was written around. Since then the catalogue has joined 1 more position to it, by shared trait or shared paper. They are listed here by the paper each came from; the text does not describe them, and each variant page carries that study's own record.
Lin SH et al. 2020, PloS one rs78119607 (near RNA5SP63) — PMID:32881892
Ewing sarcoma is diagnosed by imaging and biopsy, confirmed by detecting the tumor's acquired EWSR1-ETS gene fusion — not by the inherited variants on this page. None of the 3 germline variants here are used by any guideline to diagnose Ewing sarcoma or select treatment.
The loci described above come from a genetic study of several hundred cases, with real evidence that they affect gene expression. They explain part of who is inherently more susceptible to developing Ewing sarcoma — they do not predict whether any one person will, and they are a different question entirely from the acquired EWSR1-ETS fusion a pathologist actually tests a tumor for.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Ewing Sarcoma comes down to these specific, well-studied positions — not a diagnosis.
The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 3 of 4 linked studies with a resolved discovery ancestry.
Databases, guidelines and references
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Ewing Sarcoma. MyGeneLog™. https://www.mygenelog.com/conditions/ewing-sarcoma
A pediatric tumor of bone and soft tissue, defined by an acquired EWSR1-ETS gene fusion, occurring predominantly in people of European ancestry.
Two specific ways, both stated by the source study. TARDBP shares structural similarity with EWSR1, half of the disease's own driver fusion gene. And EGR2 is a direct target gene the fusion protein switches on -- an inherited variant near EGR2 sits beside a gene the acquired mutation itself activates.
Not fully resolved, but the genetic study behind this page found the major inherited risk haplotypes at its three loci are less common in African ancestry -- a possible, partial genetic explanation for the disease's already-known lower incidence in that population.
No. Ewing sarcoma is diagnosed by imaging, biopsy and detecting the tumor's own acquired gene fusion. These are population-level genetic findings, not a way to predict an individual case of this rare cancer.
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