International Journal of Molecular Medical Science, 2024, Vol.14, No.5, 264-273 http://medscipublisher.com/index.php/ijmms 4 can impede early detection and precise risk stratification (Ntanasis-Stathopoulos et al., 2020). This highlights the need for more advanced screening approaches that incorporate genetic markers to better identify women at high risk for cervical cancer, ultimately improving early detection and reducing the incidence of overtreatment. 3 Genetic Markers Linked to Cervical Cancer 3.1 HPV-related genetic mutations Persistent infection with high-risk human papillomavirus (HPV) types, particularly HPV16 and HPV18, is recognized as the primary cause of cervical cancer (Table 1). The integration of the viral genome into the host cell DNA disrupts regulatory genes and leads to the overexpression of viral oncoproteins E6 and E7, resulting in the inactivation of tumor suppressor proteins like p53 and retinoblastoma protein (pRb) (Keating et al., 2001). This process initiates a cascade of genetic changes within the host cell, contributing to the development of precancerous lesions and invasive cervical cancer. Recent research has identified several host cell genes that are upregulated in association with HPV infection, acting as potential surrogate markers for HPV-related epithelial lesions. For example, genes involved in cell cycle regulation, such as TP53, CDKN2A, and MYC, show mutations or altered expression in HPV-positive cervical cancer cases, helping to identify individuals at high risk for cancer progression (Salama et al., 2022). These genetic alterations offer insights into the mechanisms of HPV-induced carcinogenesis and present promising targets for early screening and risk stratification. Table 1 Clinically Important HPV Genotypes (Adopted from Rerucha et al., 2018) Genotype Pathogenesis Commonly used FDA-approved HPV tests for genotype detection and specification High risk (oncogenic) Type 16 Causes 50% of all squamous cell carcinomas of the cervix and 55% to 60% of all cervical cancers worldwide Pooled detection by Hybrid Capture II HPV DNA test, Cervista HPV DNA test, and Aptima HPV mRNA test. Specific detection by Cobas HPV DNA test Type 18 Causes 20% of cervical adenocarcinomas Pooled detection by Hybrid Capture II HPV DNA test, Cervista HPV DNA test, and Aptima HPV mRNA test. Specific detection by Cobas HPV DNA test Other: types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, (66), 68 All types combined cause 25% of cervical cancers Results are not differentiated by type and are reported as positive or negative for these 12 high-risk HPV strains. Pooled detection of all types except for type 66 by Hybrid Capture II HPV DNA test. Pooled detection of all 14 oncogenic types by Cervista HPV DNA test, Cobas HPV DNA test, and Aptima HPV mRNA test Low risk (wart-causing) Types 6 and 11 Cause 90% to 95% of anogenital warts Testing is not recommended 3.2 Epigenetic changes In addition to direct genetic mutations, epigenetic modifications like DNA methylation play a crucial role in the development of cervical cancer. HPV infection can induce epigenetic changes in both the viral and host genomes, resulting in the silencing of tumor suppressor genes and the activation of oncogenic pathways. Methylation of specific gene promoters, including those of tumor suppressor genes such as CDH1, MGMT, and DAPK, has been linked to the development of cervical cancer (Reis et al., 2020). Studies indicate that detecting DNA methylation markers in cervical cells can be an effective triage tool for identifying women with high-grade cervical intraepithelial neoplasia (CIN2+) among HPV-positive individuals. Additionally, methylation of the HPV genome itself, particularly in the L1 and L2 regions, has been associated with the persistence of HPV infection and progression to cervical cancer (Zhang et al., 2022). These epigenetic markers provide a non-invasive approach for early detection, potentially enhancing the specificity of cervical cancer screening and reducing unnecessary interventions.
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