Emerging Insights into Comparative Genetic Mutations in HPV-Associated and HPV-Independent Cervical Cancer: A Systematic Review.

Objective

Cervical cancer remains a major global health burden and is predominantly associated with human papillomavirus (HPV) infection. However, a subset of tumors develops independently of HPV, and their molecular characteristics are not fully understood. This study aimed to synthesize and compare the frequency of somatic mutations across key oncogenic pathways, p53, PI3K-Akt-mTOR, AMPK, and Ras-Raf-MAPK, in HPV-associated and HPV-independent cervical cancers.

Methods

A systematic review was conducted following PRISMA guidelines and registered in PROSPERO (CRD420251044316). Comprehensive searches were performed in PubMed, EMBASE, LILACS, Web of Science, Scopus, CINAHL, and Cochrane Central from January 2016 to March 2025 using controlled descriptors related to cervical cancer, somatic mutations, and HPV status. Eligible studies included observational designs reporting cervical cancers with molecular HPV testing and somatic mutation profiling. Data extraction was conducted independently by multiple reviewers and validated by a senior author. Study quality was assessed using STROBE criteria. Extracted variables encompassed sample characteristics, HPV status, sequencing method, genes assessed, and mutation frequencies.

Results

Eleven studies comprising 3,479 cervical cancer samples met the inclusion criteria, including 468 (13.4%) HPV-independent tumors. HPV-independent cancers demonstrated higher frequencies of TP53 and CDKN2A mutations, reaching up to 50% and 37.5%, respectively. Alterations in the PI3K-Akt-mTOR pathway, particularly PIK3CA and PTEN, showed heterogeneous patterns, with some studies reporting higher prevalence in HPV-independent tumors and others in HPV-associated tumors. Mutations in ERBB3, NTRK1, ITGB3, TSC2, and TERT were more frequent in HPV-associated cancers, while NTRK3 and RICTOR alterations appeared more common in HPV-independent tumors, although these findings were generally reported in isolated studies. Inconsistencies were also observed for STK11 (AMPK pathway) and KRAS (Ras-Raf-MAPK pathway). Considerable methodological variability limited cross-study comparability.

Conclusions

HPV-independent cervical cancers may represent a distinct molecular subgroup, particularly regarding the p53 pathway; however, study heterogeneity limits firm conclusions. Further standardized genomic studies are needed.