Long-read DNA sequencing reveals global hypomethylation and focal hypermethylation in SDHx-deficient pheochromocytoma and paraganglioma

Long-read methylome profiling shows both SDHx-deficient and non-SDHx pheochromocytoma/paraganglioma tumors are globally hypomethylated, especially at centromeres.

• Why it matters: Tumor DNA is often hypomethylated, but SDHx-related PPGLs have been reported as hypermethylated; the study addresses this mismatch in methylation patterns.
• What they did: Using nanopore long-read sequencing, the authors compared methylation in tumor and white blood cell DNA from SDHx and non-SDHx PPGL patients and normal adrenal medulla.
• The result: In normal adrenal medulla, H3K4-marked CpG islands are hypomethylated while H3K4-lacking islands are hypermethylated; in SDHx-related PPGL, only some H3K4-marked islands become hypermethylated, suggesting succinate-mediated TET inhibition partly offsets global tumor hypomethylation.

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