Cervical Cancer Stages, Human Papillomavirus Integration, and Malignant Genetic Mutations: Integrative Analysis of Datasets from Four Different Cohorts

Abstract

Cervical cancer represents a significant global health concern, stemming from persistent infections with high-risk types of human papillomavirus (HPV). The understanding of cervical cancer's clinical correlates, risk factors, molecular mechanisms, stages, and associated genetic mutations is important for early detection and improved treatment strategies. Through integrated analysis of clinical and molecular datasets, this study aims to identify key factors that are overlapping and distinct across four cohorts of different races and regions. Here, datasets from four distinct cohorts of patients from Uganda (N = 212), the United States of America (USA) (N = 228), China (N = 106), and Venezuela (N = 858) were examined to comprehensively explore the relationships between cervical cancer stages, HPV types (clades), productive HPV integration, and malignant genetic mutations. Cohort-specific findings included the occurrence frequencies of cervical cancer stages and grades. The majority of patients from the USA and China were diagnosed with stages I and II, while those from Uganda were diagnosed with stages II and III, reflecting levels of awareness and the availability of HPV vaccines and screening services. Conversely, cervical cancer and its stages were positively correlated with HPV types (clades), HPV integration, and risk-factor habits across the cohorts. Our findings indicate that the more common squamous cervical cancer can be potentially due to productive HPV16 (clade 9) integration. At the molecular level, pathways related to HPV infection, cancer-related conditions, and viral carcinogenesis were among the most significant pathways associated with mutated genes in cervical cancer (across cohorts). These findings collectively corroborate the prominent role of HPV infection and integration leading to genetic mutation and hence to the development of cervical cancer and its stages across patients of distinct races and regions.

Keywords: cervical cancer; human papillomavirus (HPV); molecular pathways; mutation; productive integration; protein networks; stages of cervical cancer.

Figure 1

Occurrence frequencies of cervical cancer stages across three cohorts of patients from the USA, China, and Uganda.

Figure 2

Distribution of clinical and demographic features across stages I, II, and III and IV of 546 cervical cancer patients (comprising three different cohorts from the USA, China, and Uganda). Patients belonging to the 31–40 and 41–50 age groups are the majority at stage I, while patients of the 51–60 age group are the majority at stage II.

Figure 3

Ranking of risk factors as predictors and clinical and demographic correlates. (a) Predictors (risk factors) for cervical cancer identified using the regularized random forest algorithm and ranked according to the MeanDecreaseGini. (b) Correlations among clinical features and HPV types with the stages of cervical cancer. Similar patterns were observed in the dataset from the Venezuelan cohort (Figure S2).

Figure 4

Protein networks and significantly associated pathways for genes that are sites of HPV integration and mutated in cervical cancer: (a) proteins significantly associated with human papillomavirus infection (yellow nodes); (b) proteins significantly associated with cancer-related conditions (yellow nodes); (c) anti-cancer drugs (diamond-shaped green nodes). Other nodes (besides the yellow colored nodes in (a,b) are shown to have functional and regulatory relations with the yellow colored nodes. Note: A cancer-related condition is a disorder either associated with an increased risk of malignant transformation (e.g., intraepithelial neoplasia, leukoplakia, dysplastic nevus, and myelodysplastic syndrome) or that develops as a result of the presence of an existing malignant neoplasm (e.g., paraneoplastic syndrome).