Ewing sarcoma: the same engine on a second cancer, built and then shelved.

Note added 2026-07-30. This post describes work done in June and its numbers are left as they were, because they record what was actually run. Two things have since changed: the DMG anchor was corrected from n=49 to n=60 (the original derivation queried the wrong HIST1H3B symbol and missed 11 H3.1 cases), and Ewing has been shelved as a selectable indication pending DMG proof-out. Read the n=49 figures below as the anchor at the time, not as the current one.

The claim we made when we shipped the DMG cohort architect in week 4 was that the engine would be indication-portable: keep the same statistical core, swap the molecular profile library and the anchor cohort, and watch it reproduce different biology in a different rare cancer.

This week we tested that claim by adding Ewing sarcoma. It worked, with one honest finding that we are reporting directly rather than hiding.

Why Ewing as the second indication

DMG and Ewing are deliberately different shapes. DMG is defined by a single-base histone mutation (H3 K27M). Ewing is defined by a recurrent structural variant: EWSR1::FLI1 in about 85% of cases, EWSR1::ERG in about 10%, other FET::ETS fusions in the rest. If one engine handles both without re-parameterisation, that is evidence of portability across very different molecular paradigms.

We anchored to two published Ewing cohorts on cBioPortal (Crompton et al., Cancer Discovery 2014, DFCI, n=107; Tirode et al., Cancer Discovery 2014, Institut Curie, n=115). Pooled anchor: n=222, about three times the DMG anchor as it stood then, n=49 (since corrected to n=60).

What the engine produces

The 200 simulated Ewing co-mutation profiles surface EWSR1::FLI1 prevalence at 86.5% (target about 85% per the literature consensus). STAG2 marginal frequency lands at 13.1% versus the 17-22% range published by Tirode 2014 and Brohl 2014, close given the public mutation profile undercounts copy-number alterations. TP53 marginal at 9.5% is squarely inside the published 7-10% range.

The honest finding

Tirode 2014's headline finding was that STAG2 and TP53 mutations co-occur in an aggressive subtype. In our n=222 extract, that pair does not reach significance on the co-occurrence test (observed 9, expected 12.3, raw p = 0.32). It actually trends toward mutual exclusivity, not co-occurrence.

We're reporting this directly in the methodology preprint instead of massaging it. The system's value depends on never burying that kind of result. If it had silently reproduced the published headline, the methodology page would have one less honesty point, and one more piece of luck to depend on.

What this gives the rest of the build

• A second indication built and validated, then shelved pending DMG proof-out and Ewing-expert review.
• A repeatable path to the next indication: the same engine, a new molecular profile library, a new anchor cohort.
• A real validation result (the STAG2+TP53 non-finding) that landed in the public methodology page and the preprint draft.
• A co-occurrence agreement figure generated from live data: DMG (n=49 at the time, now n=60) shows wider scatter than Ewing (n=222), exactly as small-n predicts.

What's next

Ewing-domain-expert review comes before any engagement-grade report uses the Ewing library. Until that review lands the Ewing library stays a draft. Indication #3 comes only after DMG is proven, most likely MPNST or ATRT, same pattern, same engine, different molecular profile library.

The full methodology supplement for this run stays in our internal notes; the preprint is in draft and not yet posted.