DNA-Damage-Repair Gene Alterations in Genitourinary Malignancies

Area of Science:

• Genitourinary Oncology
• Genomic Integrity and DNA Repair
• Precision Medicine

Background:

• High-fidelity DNA damage repair (DDR), including single-strand break (SSB) and double-strand break (DSB) repair, is vital for genomic stability and cell survival.
• Alterations in DDR pathways, particularly homologous recombination repair (HRR) and poly (ADP-ribose) polymerase (PARP) pathways, are prevalent in genitourinary malignancies.
• PARP inhibitors (PARPi) leverage synthetic lethality by targeting cells with HR-deficient (HRD) DNA repair mechanisms.

Purpose of the Study:

• To highlight the importance of identifying germinal and somatic DDR alterations in patients with genitourinary cancers.
• To underscore the therapeutic potential of PARP inhibitors (PARPi) in these malignancies.
• To discuss the role of DDR gene status as a biomarker for treatment selection and eligibility for PARPi therapy.

Main Methods:

• Review of existing evidence on DDR alterations in genitourinary cancers.
• Analysis of clinical trial data and preclinical findings regarding PARPi efficacy.
• Evaluation of the association between DDR gene status and treatment response.

Main Results:

• Somatic HRR mutations are found in up to 27% of metastatic castration-resistant prostate cancer (mCRPC), with BRCA2, ATM, CHEK2, and BRCA1 being commonly affected.
• Germline alterations in DDR genes are present in 30-50% of HRR alteration cases, with BRCA2 carriers having a significantly higher risk of prostate cancer.
• DDR gene alterations are identified in 23-54% of urothelial carcinoma patients and recurrently in advanced renal cell carcinomas (RCCs).

Conclusions:

• Identifying DDR alterations is essential for guiding treatment decisions in genitourinary malignancies.
• PARPi, such as olaparib, have demonstrated significant survival benefits in patients with HRR-mutated advanced cancers, supporting their use in precision medicine.
• DDR gene status can serve as a predictive biomarker for response to therapies like androgen-receptor signaling inhibitors (ARSI), chemotherapy, and immunotherapy, and for PARPi eligibility.