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Abstract
Molecular diagnostics has become an integral part of prostate cancer (PrCa) management. Genetic tests are used for the analysis of germline mutations associated with hereditary cancer syndromes, as well as for therapy selection. There are some controversies regarding the use and interpretation of molecular genetic assays. In particular, in studies and clinical guidelines, BRCA1 and BRCA2 genes are commonly grouped together, although the PrCa-predisposing role and predictive significance for the benefit from poly(ADP-ribose) polymerase inhibitors (PARPi) have been shown mainly for BRCA2, but not for BRCA1 alterations.
The use of PARPi relies on mutation analysis in homologous recombination repair (HRR) genes. However, clinical trial results do not confirm the predictive role of defects in some HRR panel genes, such as ATM, CHEK2, and CDK12. Sensitivity to PARPi therapy is associated with biallelic rather than monoallelic inactivation of specific HRR genes, yet this aspect is currently not considered in drug labels or clinical guidelines. Homologous recombination deficiency (HRD) testing, which analyzes chromosomal instability in tumors, is widely used in ovarian cancer. This assay has an advantage over HRR analysis as it determines not the potential causes of genomic instability, but the actual inability of tumor cells to repair DNA double-strand breaks. Microsatellite instability (MSI) occurs in 3-5% of PrCa cases, necessitating Lynch syndrome testing and enabling immunotherapy use. However, the application of MSI testing in real-world clinical practice for PrCa seems to be underrepresented.
References
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