Cancer Genetics and Epigenetics 2024, Vol.12, No.2, 79-87 http://medscipublisher.com/index.php/cge 80 also explores the genetic diversity of PCa among different populations, emphasizing the importance of including diverse racial groups in genomic research to uncover population-specific genetic drivers of the disease. 2 Advances in Whole-Genome Sequencing of Prostate Cancer 2.1 Identification of genetic mutations Whole-genome sequencing (WGS) has significantly advanced our understanding of the genetic mutations associated with prostate cancer. Key mutations identified through WGS include alterations in genes such as CHD1, BRCA2, and androgen receptor (AR) upstream activator genes. For instance, a study on Chinese prostate cancer patients revealed a high frequency of CHD1 deletions and mutations in androgen receptor upstream activator genes, which are associated with disease progression (Ren et al., 2017). Additionally, WGS has uncovered 22 previously unidentified putative driver genes, including NEAT1 and FOXA1, which act as drivers through noncoding mutations (Wedge et al., 2018). These findings highlight the complexity and diversity of genetic alterations in prostate cancer, providing new insights into the molecular mechanisms driving the disease. 2.2 Insights into tumor heterogeneity WGS has also provided valuable insights into the heterogeneity of prostate tumors. Intra-tumor and inter-tumor heterogeneity have been extensively studied, revealing significant variations in genetic alterations within and between tumors. For example, a study using targeted next-generation sequencing of advanced prostate cancer identified substantial heterogeneity in genomic alterations, including AR copy number gain, TMPRSS2-ERG fusion, and PTEN loss (Beltran et al., 2013; Bewicke-Copley et al., 2019). This heterogeneity has important implications for treatment and prognosis, as it suggests that personalized treatment strategies may be necessary to effectively target the diverse genetic landscape of prostate cancer. 2.3 Discovery of new biomarkers The discovery of new biomarkers through WGS has opened up new avenues for early detection and prognosis of prostate cancer. Biomarkers such as PCDH9 and PLXNA1 have been identified as potential prognostic indicators. PCDH9, which is deleted or lost in approximately 23% of tumors, functions as a novel tumor suppressor gene with prognostic potential (Ren et al., 2017). Similarly, the gain/amplification of the PLXNA1 gene, observed in approximately 17% of tumors, has been shown to promote prostate tumor growth and predict poor survival outcomes (Ren et al., 2017). These biomarkers have potential clinical applications in improving the diagnosis, prognosis, and treatment of prostate cancer. 3 Clinical Applications and Implications 3.1 Personalized medicine 3.1.1 Role of WGS in developing personalized treatment plans Whole-genome sequencing has significantly advanced the field of personalized medicine by enabling the identification of unique genetic alterations in individual prostate cancer patients. This allows for the development of tailored treatment plans that target specific mutations and pathways involved in the patient's cancer. For instance, WGS has been used to identify mutations in DNA damage response genes, PI3K, MAPK, and Wnt pathways, which can inform the use of targeted therapies such as PARP inhibitors and immunotherapy (Ciccarese et al., 2017; Crumbaker et al., 2020). Additionally, the integration of WGS with other sequencing methods, such as whole-exome sequencing (WES) and RNA sequencing (RNAseq), has been shown to provide a comprehensive mutational landscape that can guide clinical decision-making (Roychowdhury et al., 2011; Nauseef et al., 2023). 3.1.2 Case studies and clinical trials Several case studies and clinical trials have demonstrated the feasibility and clinical utility of WGS in personalized medicine for prostate cancer. For example, a study involving 34 patients with advanced cancers utilized WGS to identify therapeutically relevant targets, leading to genomic-directed treatments in 10 patients, with preliminary clinical efficacy observed in four patients (Borad et al., 2013). Another study highlighted the use of WGS in a patient with advanced prostate cancer, where the identification of an SPOP mutation and androgen-receptor dependency informed a successful personalized treatment approach (Figure 1) (Armstrong et
RkJQdWJsaXNoZXIy MjQ4ODYzNQ==