Cancer Genetics and Epigenetics 2024, Vol.12, No.2, 79-87 http://medscipublisher.com/index.php/cge 82 therapeutically relevant alterations, including those associated with PARP inhibitor sensitivity and resistance to androgen pathway targeting agents (Figure 2) (Crumbaker et al., 2020). Another study showed that the integration of WGS with clinical data could identify molecular signatures associated with homologous recombination deficiency and mismatch repair deficiency, which have prognostic implications for treatment response and disease progression (Nauseef et al., 2023). These findings highlight the potential of WGS to provide prognostic insights that can guide clinical management and improve patient outcomes. Figure 2 Summary of genomic alterations in primary prostate samples with synchronous lymph node metastases (Cases 19011, 19260 and 19145) (Adopted from Crumbaker et al., 2020) In conclusion, WGS has emerged as a powerful tool in the clinical management of prostate cancer, offering significant advances in personalized medicine, targeted therapies, and predictive and prognostic value. The continued integration of WGS into clinical practice holds promise for improving the diagnosis, treatment, and outcomes of prostate cancer patients. 4 Challenges and Limitations 4.1 Technical and analytical challenges Whole-genome sequencing (WGS) of prostate cancer presents several technical and analytical challenges. One significant issue is the difficulty in obtaining sufficient high-quality DNA from metastatic tissues, which are often limited in availability and quality. This is particularly problematic for advanced prostate cancer, where metastatic tissue is crucial for comprehensive genomic analysis (Beltran et al., 2013; Lohr et al., 2014). Additionally, the isolation and sequencing of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) require overcoming the challenges of isolating rare cells and sequencing low-input material, which can lead to incomplete or biased genomic data (Lohr et al., 2014; Sumanasuriya et al., 2021). Furthermore, the complexity of prostate cancer genomes, characterized by a high degree of heterogeneity and the presence of both coding and non-coding mutations, complicates the identification and interpretation of driver mutations and other clinically relevant alterations (Robinson et al., 2015; Ren et al, 2017; Wedge et al., 2018). 4.2 Clinical and ethical considerations The clinical application of WGS in prostate cancer is fraught with ethical and practical considerations. One major concern is the interpretation and communication of incidental findings, which may have significant implications for patients and their families. The identification of germline mutations, for instance, can reveal hereditary cancer syndromes that necessitate genetic counseling and potential testing of family members (Abida et al., 2017). Additionally, the clinical utility of WGS data is still under investigation, and there is a need for robust clinical trials to validate the prognostic and therapeutic relevance of identified genomic alterations (Beltran et al., 2015). Ethical considerations also include the potential for genetic discrimination and the need for informed consent processes that adequately explain the risks and benefits of WGS to patients (Beltran et al., 2015; Abida et al., 2017).
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