Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 223-233 http://medscipublisher.com/index.php/cge 225 Figure 1 The hypoxia-inducible transcription factor (HIF) pathway in clear cell renal cancer (Adopted from Schödel et al., 2016) Image caption: In normal epithelial cells, ubiquitination of HIF-α by the E3 ubiquitin ligase leads to degradation via the 26 proteasome. In precancerous cells, defective tumor suppressor pVHL or elongin C results in stabilization of both HIF-α isoforms. Subsequent deletions of HIF-1α and/or chromatin-modifying enzymes as well as somatic mutations in HIF DNA-binding sites can affect the transcriptional program of HIF and eventually lead to a tumorigenic phenotype; eloB = elongin B; eloC = elongin C; HIF = hypoxia-inducible transcription factors; VHL = von Hippel-Lindau protein (Adopted from Schödel et al., 2016) 2.3 Epidemiology of VHL mutations in RCC The prevalence of VHL mutations in RCC varies across different populations and subtypes of kidney cancer. In ccRCC, VHL mutations are found in approximately 70-90% of cases, making it one of the most common genetic alterations in this subtype (Turner et al., 2002; Schödel et al., 2016; Kim et al., 2021). These mutations are less frequent in other subtypes of RCC, such as papillary and chromophobe RCC, highlighting the specific role of VHL in ccRCC pathogenesis (Turner et al., 2002). Studies have shown that the presence of VHL mutations correlates with specific clinical and pathological features of ccRCC. For example, tumors with biallelic inactivation of VHL often exhibit higher levels of HIF-2α and increased expression of PD-L1, which may influence the response to immunotherapy (Messai et al., 2016). Additionally, the type and location of VHL mutations can impact the stability and activity of HIF-α subunits, further modulating the tumor phenotype and progression (Turner et al., 2002; Ordóñez-Navadijo et al., 2016; Schödel et al., 2016). In summary, the VHLgene plays a pivotal role in the pathogenesis of kidney cancer, particularly ccRCC, through its regulation of HIFs and other cellular processes. Mutations in VHL lead to the dysregulation of hypoxia pathways, contributing to tumor development and progression. Understanding the epidemiology and functional consequences of VHL mutations is essential for developing targeted therapies and improving clinical outcomes for RCC patients. 3 Diagnostic Technologies for VHL Mutation Detection 3.1 Molecular techniques for VHLgene analysis The detection of VHL mutations in kidney cancer, particularly clear cell renal cell carcinoma (ccRCC), employs several molecular techniques. Polymerase Chain Reaction (PCR) is a fundamental method used to amplify DNA sequences, making it easier to identify mutations. Single-strand conformation polymorphism analysis and sequencing are also commonly used to detect specific mutations within the VHL gene (Brauch et al., 2000). Sequencing, including Sanger sequencing, provides detailed information about the genetic alterations by determining the exact nucleotide sequence of the VHL gene (Nickerson et al., 2008). Additionally, methylation-specific assays are employed to detect hypermethylation in the VHL promoter region, which can lead to gene silencing (Herman et al., 1994). These techniques collectively help in identifying both genetic and
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