Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer
Rebeca Lozano1,2, Elena Castro1,2,3, Isabel M Aragón1,2
1Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Abstract:
Over the past years, several studies have demonstrated that defects in DNA damage response and repair (DDR) genes are present in a significant proportion of patients with prostate cancer. These alterations, particularly mutations in BRCA2, are known to be associated with an increased risk of developing prostate cancer and more aggressive forms of the disease. There is growing evidence that certain DDR gene aberrations confer sensitivity to poly-(ADP ribose) polymerase inhibitors and/or platinum chemotherapy, while other defects might identify cases that are more likely to benefit from immune checkpoint inhibition. The potential prognostic impact and relevance for treatment selection together with the decreasing costs and broader accessibility to next-generation sequencing have already resulted in the increased frequency of genetic profiling of prostate tumours. Remarkably, almost half of all DDR genetic defects can occur in the germline, and prostate cancer patients identified as mutation carriers, as well as their families, will require appropriate genetic counselling. In this review, we summarise the current knowledge regarding the biology and clinical implications of DDR defects in prostate cancer, and outline how this evidence is prompting a change in the treatment landscape of the disease.
Insights
Defects in DNA damage response and repair (DDR) genes are common in prostate cancer, impacting risk and aggression. Understanding these DDR gene alterations guides treatment selection and offers prognostic insights.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Defects in DNA damage response and repair (DDR) genes are frequently observed in prostate cancer patients.
- Mutations in genes like BRCA2 are linked to higher prostate cancer risk and increased disease aggressiveness.
Purpose of the Study:
- To review the biological and clinical implications of DDR gene defects in prostate cancer.
- To explore how DDR alterations influence treatment strategies and patient outcomes.
Main Methods:
- Literature review of studies on DDR gene defects in prostate cancer.
- Analysis of genetic profiling data and its correlation with clinical outcomes.
- Examination of therapeutic sensitivities associated with specific DDR aberrations.
Main Results:
- DDR gene defects are prevalent in prostate cancer, with nearly half being germline mutations.
- Specific DDR aberrations predict sensitivity to PARP inhibitors, platinum chemotherapy, or immune checkpoint inhibitors.
- Genetic profiling of prostate tumors is increasing due to its prognostic and therapeutic relevance.
Conclusions:
- DDR gene defects play a crucial role in prostate cancer development and progression.
- Identifying DDR alterations is essential for personalized treatment selection and risk stratification.
- Advances in genetic testing are transforming prostate cancer management and treatment paradigms.
Related Concept Videos
01:38Nucleotide Excision Repair
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
01:08Nucleotide Excision Repair
01:54Base Excision Repair
The first step of...
01:54Base Excision Repair
01:20Mismatch Repair
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
01:36Mismatch Repair