DNA Damage Repair Pathways in Prostate Cancer: A Narrative Review of Molecular Mechanisms, Emerging Biomarkers and...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Prostate cancer (PCa) exhibits a unique molecular profile, including DNA damage repair defects.
• Homologous recombination deficiency (HRD) affects nearly 20% of metastatic castrate-resistant PCa (mCRPC) and is linked to hereditary predisposition and aggressive disease.
• Key genes involved in HRD include BRCA2, ATM, and CHECK2, with BRCA2 mutations correlating to unfavorable tumor characteristics.

Purpose of the Study:

• To review the role of DNA damage repair pathways in prostate cancer.
• To highlight therapeutic strategies targeting these pathways, such as PARP inhibitors for HRD-altered mCRPC.
• To discuss the significance of mismatch repair (MMR) deficiency and potential biomarkers in PCa.

Main Methods:

• Literature review of studies on DNA damage repair mechanisms in prostate cancer.
• Analysis of genetic mutations (e.g., BRCA2, ATM, CHECK2) and their clinical implications.
• Evaluation of therapeutic agents (e.g., PARP inhibitors, PD-1 inhibitors) and biomarkers (e.g., tumor mutational burden, PDL-1).

Main Results:

• HRD is a significant factor in mCRPC, with approved PARP inhibitor therapies.
• Germline mutations in HRD genes predispose to early and aggressive PCa.
• Mismatch repair (MMR) deficiency, found in 5% of metastatic PCa, is associated with aggressive disease and sensitivity to PD-1 inhibitors.

Conclusions:

• DNA damage repair pathways, including HRD and MMR, are critical in prostate cancer progression and treatment response.
• Targeting HRD with PARP inhibitors and MMR deficiency with PD-1 inhibitors represents important therapeutic strategies.
• Further research into DNA damage pathways may uncover novel biomarkers and therapeutic targets for PCa.