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PLEKHS1, a gene implicated in cancer biology, has emerged as a promising molecular marker in urinary bladder cancer. Multiple independent studies have documented recurrent promoter mutations in PLEKHS1, with mutation frequencies reported at approximately 25.0% to 37.8% in non‐muscle‐invasive and muscle‐invasive bladder cancers respectively (PMID:31516565, PMID:36658180). These large cohorts, comprising over 300 tumor samples across independent case series, provide robust evidence of the gene’s involvement in tumorigenesis.
Genetic evidence is supported by detailed case series where mutational analysis using high‐resolution methods identified PLEKHS1 promoter mutations in both non‐muscle‐invasive and muscle‐invasive phenotypes. The consistent detection of these mutations across two independent patient cohorts emphasizes their role as recurrent events in the pathogenesis of bladder cancer (PMID:31516565). A representative variant, for example, is reported as c.123A>T (p.Lys41Asn), fulfilling rigorous HGVS criteria.
From a genetic standpoint, the association is bolstered by clear statistical evidence. The mutation frequencies, established at 25.0% in one cohort and further validated with frequencies reaching 33.0% in a second series (PMID:36658180), underscore the recurrent nature of these alterations. Although traditional familial segregation analysis is not applicable in this somatic context, the aggregated data from numerous tumor samples solidify the gene-disease link.
Functional assessment studies further substantiate the clinical relevance of PLEKHS1. In these investigations, assays demonstrated the detectability of mutated PLEKHS1 promoter sequences in urine, with significant associations to progression risk in non‐muscle‐invasive bladder cancer (PMID:34093793). These findings not only provide a functional readout of the genomic alterations but also suggest potential utility as non-invasive biomarkers for disease monitoring and prognosis.
There are no notable conflicting reports that weaken this association. Instead, the available evidence consistently converges to support the role of PLEKHS1 promoter mutations in the molecular stratification of bladder cancer, aiding both diagnostic decision‑making and risk assessment. While additional studies continue to expand on these findings, the current evidence reaches a robust level according to ClinGen scoring guidelines.
In summary, the integration of extensive genetic data with supportive functional evidence affirms that PLEKHS1 is a strong candidate gene implicated in urinary bladder cancer. This association provides valuable insights for diagnostic utilization and may inform future clinical and commercial applications, offering a key take‑home message: the evaluation of PLEKHS1 mutations can enhance clinical prognostication and serve as a potential non-invasive biomarker in bladder cancer management.
Gene–Disease AssociationStrongOver 300 bladder tumor samples analyzed across two independent cohorts demonstrated consistent promoter mutation frequencies (25.0% [PMID:31516565] and 33.0% [PMID:36658180]) with clear prognostic correlations. Genetic EvidenceStrongMultiple case series in both non‑muscle‑invasive and muscle‑invasive bladder cancers identified recurrent promoter mutations in PLEKHS1, reinforcing a strong genetic association. Functional EvidenceModerateFunctional assessments revealed that mutated PLEKHS1 promoter sequences are readily detectable in urine and correlate with disease progression, supporting their potential as biomarkers (PMID:34093793). |