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  "path": "/t/thinking-clearly-about-association-studies-risk-factors-and-causal-salad-included/28679?page=2#post_30",
  "publishedAt": "2026-04-07T00:00:32.000Z",
  "site": "https://discourse.datamethods.org",
  "tags": [
    "here is a case report",
    "recently showed here",
    "survival outcomes are improving",
    "overall weak signal of efficacy in RMC"
  ],
  "textContent": "On a related note, here is a case report we published last year on a potential safety signal with this EZH2 inhibitor (tazemetostat) in a patient with SMARCB1-deficient renal medullary carcinoma (RMC) who was treated with tazemetostat and subsequently developed a brain metastasis whose morphology, immunohistochemistry, and methylation profile had drifted toward a glial phenotype while still carrying the same PPP2R5E::KLC1 fusion and SMARCB1 loss as the pre-treatment tumor, largely confirming clonal identity. So the same tumor lineage appeared to have undergone glial transdifferentiation after exposure to an epigenetic modulator.\n\nThe mechanistic story is appealing: EZH2 inhibition by tazemetostat relaxes H3K27me3-mediated lineage constraints, SMARCB1-null RMC cells already sit on a precarious epigenetic landscape as we also recently showed here.\n\nBut, sticking to the point of this thread, this is exactly the setting where one should be most disciplined as we have a single patient, an unmeasured counterfactual, and a temporal association that could just as easily reflect natural history of an aggressive tumor with rare CNS tropism whose survival outcomes are improving thanks to our ongoing research efforts. We thus tried to be careful in the paper to frame it as a hypothesis-generating observation rather than evidence that tazemetostat _caused_ the transdifferentiation, and I think it’s a useful concrete example of a case that is descriptively striking (glial mimicry was previously unheard of – certainly in RMC) but causally only a conjecture.\n\nWith tazemetostat now off the market, and its overall weak signal of efficacy in RMC, it is unlikely that much more data points will be generated in this setting.",
  "title": "Thinking Clearly about Association Studies (Risk Factors and Causal Salad included)"
}