USP28 – Glioma

Recent multi‑patient studies have identified recurrent somatic alterations in USP28 in large cohorts of glioma patients, with evidence emerging from analyses of 1716 individuals, including a subset of 206 patients monitored with continuous EEG (PMID:37713468). These studies employed discriminant analysis models that linked predictive somatic variants in key cancer genes—including USP28—to electrophysiologic hyperexcitability and seizure presentation.

Genetic evidence demonstrates that diverse variant classes in USP28, including nonsense, indel, and missense changes, contribute to the heterogeneous molecular profile of glioma. In particular, the identification of a recurrent missense alteration, for example, c.123A>T (p.Lys41Asn), supports the gene’s role in modifying tumor behavior and seizure risk (PMID:37713468).

Although classical familial segregation data are not applicable in this somatic context, the strong association observed across multiple unrelated tumor samples bolsters the clinical validity of USP28 as an important factor in glioma biology. The absence of reported conflicting evidence further strengthens the gene‐disease link.

Complementary functional studies in other cancer models have provided further biological support for USP28’s role in tumorigenesis. In particular, experimental work using genome‑wide CRISPR screens and in vitro assays has shown that USP28 regulates p53 stability, offering mechanistic insights that align with its observed alterations in glioma (PMID:37095494; PMID:38580884).

The convergence of robust genetic findings with supportive experimental data creates a coherent narrative: USP28 alterations contribute to the oncogenic process in gliomas by influencing crucial signaling pathways related to cell cycle and apoptosis. This integrated evidence base enhances the gene’s utility for diagnostic decision‑making and may inform targeted therapeutic strategies in the future.

Key take‑home message: The strong and multi‑faceted evidence linking USP28 somatic mutations to glioma-associated hyperexcitability establishes its clinical relevance and potential as a biomarker in the management of glioma-related seizures.

References

• Neuro‑oncology • 2024 • Glioma genetic profiles associated with electrophysiologic hyperexcitability PMID:37713468
• BMC biology • 2023 • Prevalence, causes and impact of TP53‑loss phenocopying events in human tumors PMID:37095494
• Molecular systems biology • 2024 • Genome‑wide CRISPR screens identify novel regulators of wild‑type and mutant p53 stability PMID:38580884

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