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In this study, EXO5, a gene encoding a DNA exonuclease critical for double-strand break repair, has been implicated in prostate cancer pathogenesis. Multiple lines of evidence support its role in tumorigenesis, including genetic findings from families with metastatic prostate cancer and thorough functional assessments. The gene’s loss of function underscores its impact on genomic stability and the fidelity of the homologous recombination repair pathway (PMID:31616062). The clinical observations provided a basis for considering EXO5 in the diagnostic evaluation of familial prostate cancer. The investigation spanned both genetic case series and functional studies, enhancing the overall confidence in this association. These findings provide a foundation for further clinical and translational applications.
Genetic evidence originates from a whole-exome sequencing study of 20 prostate cancer families, in which at least three siblings per family were diagnosed with metastatic prostate cancer (PMID:31616062). Among the genes interrogated, the c.452T>C (p.Leu151Pro) variant in EXO5 was consistently detected in all affected siblings in three separate families. This segregation pattern, although observed in a subset of families, contributes significantly to the genetic validation of the disease association. The recurrence of the variant in unrelated individuals, along with significant SNP associations from dbGaP datasets, strongly supports its pathogenic role. These data collectively implicate EXO5 as a driver in prostate tumorigenesis. The genetic clustering of the variant confirms its diagnostic relevance in familial cases.
The single recurrent variant, c.452T>C (p.Leu151Pro), has been instrumental in linking EXO5 to prostate cancer. This variant, which alters a highly conserved leucine residue, has been shown to compromise the exonuclease's function. In silico and bioinformatics analyses predict this missense change to be deleterious, affirming its potential to impair protein structure and catalytic activity (PMID:31616062). The evidence was further augmented by comparative studies demonstrating the conservation of the L151 residue across species. Additionally, the observed linkage disequilibrium with other risk SNPs adds an extra layer of validation. Taken together, the variant’s recurrence and predicted functional impact underscore its utility as a molecular marker.
Functional studies add a compelling dimension to the association by demonstrating that the L151P substitution significantly impairs the DNA repair capacity of EXO5. CRISPR-mediated knockout experiments in prostate cancer cell lines resulted in marked decreases in homology-directed repair efficiency, leading to androgen-induced genomic instability and aberrant transcripts such as TMPRSS2-ERG (PMID:31616062). Moreover, molecular dynamics simulations have revealed that the L151P mutation disrupts the catalytic domain, altering both the protein’s conformation and nuclear localization (PMID:40115981). Complementary functional studies using evolutionary trace and action scoring further substantiate the pathogenic effect of this mutation (PMID:34966786). These experimental results robustly extend the genetic findings and firmly establish the functional deficits arising from the EXO5 mutation.
Integrating the genetic and experimental data provides a robust narrative where EXO5’s recurrent c.452T>C (p.Leu151Pro) variant leads to compromised DNA repair, which in turn precipitates androgen-induced genomic instability and prostate tumorigenesis. Both the segregation analyses from multi-patient studies and the mechanistic insights from functional assays converge on a strong gene-disease relationship. Although additional genetic modifiers and environmental factors may modulate disease penetrance, the current evidence decisively supports a strong clinical association. Thus, EXO5 mutation screening offers potential not only for risk assessment and diagnostic refinement but also for informing precision therapeutic strategies in prostate cancer.
Key Take‑Home: The strong integration of multi‑family genetic segregation data with robust functional validation establishes EXO5, and specifically the c.452T>C (p.Leu151Pro) variant, as a clinically actionable marker for prostate cancer risk, underscoring its utility in diagnostic and precision medicine approaches.
Gene–Disease AssociationStrongAssociation supported by segregation in three families with multiple affected siblings (PMID:31616062) and corroborated by functional experiments demonstrating impaired DNA repair. Genetic EvidenceStrongThe recurrent c.452T>C (p.Leu151Pro) variant observed in multiple affected individuals among 20 PCa families, along with supportive SNP associations, solidifies the genetic linkage. Functional EvidenceStrongRobust functional data from CRISPR-mediated knockouts, DNA repair assays, and molecular dynamics simulations demonstrate that the L151P mutation disrupts EXO5 activity and nuclear localization. |