Investigating the DNA Methylome of Prostate Cancer in a Ghanaian Cohort and Novel Pathways that Link Schistosome Infections to Prostate Cancer

Abstract

Prostate cancer (PCa) is of significant public health concern in Africa. The incidence and mortality rates are notably higher, and the disease often presents at a more advanced stage. This disparity is influenced by a combination of genetic, environmental, and lifestyle factors that are not yet fully understood. DNA methylation studies offer a promising avenue for understanding the epigenetic changes that promote PCa risk and progression. Additionally, the study of schistosomes, parasitic flatworms prevalent in Africa and previously associated with bladder cancer, is crucial as they have been associated with and represent a potential risk factor for PCa development. The present study aimed at profiling the DNA methylation patterns of PCa in sub-Saharan African men and schistosome infections as a potential risk factor for PCa. The study used the Illumina Infinium EPIC array, a high throughput state-of-the-art platform to profile the DNA methylation profile of the study cohort. To evaluate schistosoma exposure as a risk factor for PCa development, a series of in vitro assays, rt-qPCR, and omics approaches (mass spectrometry) were employed. A high degree of interindividual heterogeneity was observed in DNA methylation patterns between benign and malignant prostate samples. This heterogeneity was attributed to the genomic diversity inherent in African populations. Notably, clustering based on tumour grade was evident, implicating cellular structure, division pathways, and oxidoreductase activities in PCa aggressiveness. Intriguingly, samples from high-grade tumours exhibited elevated levels of luminal cells, suggesting that inflammatory stimuli, potentially from oxidative stress, mechanical injury or infectious agents like Schistosoma haematobium, could contribute to PCa aggressiveness. Given Africa's high burden of schistosomiasis, the study further explored the role of Schistosoma spp in PCa development. Network propagation techniques were employed, identifying several pathways that could be exploited by the parasites to induce carcinogenesis, including clathrin mediated endocytosis, alpha defensins and degradation and organization of the extracellular matrix. In vitro assays and multi-omics approaches used to validate the predictions on the pathways perturbed by schistosome exposure of normal prostate epithelial cells revealed several insights. Firstly, significant dose-dependent cell proliferation was observed, particularly with schistosome soluble egg antigens from S. haematobium or S. haematobium plus S. mansoni (schSEAh and schSEAc). Secondly, elevated levels of proinflammatory cytokines and angiogenic markers were also noted, supporting the hypothesis that schistosome infections could induce chronic inflammation and promote vascularization, key elements in cancer development. Finally, schSEA treatments triggered differentially expressed proteins (DEPs) associated with proteins associated with cellular metabolism and cell cycle. Metabolic reprogramming and cell cycle alterations are known to be involved in prostate cancer development and progression. Differential expression of MX2, NSUN2 and DLG1 correlated with high alteration frequencies in their corresponding genes in publicly available in TCGA PCa genomic data. Despite its insights, the study acknowledges limitations such as the small sample size for DNA methylation profiling and the absence of long-term in vitro exposure models. Future research would aim to address these gaps to provide a more conclusive understanding of the DNA methylation profile of PCa in Africa and a robust understanding of the complex interplay between schistosome infections and PCa development in African men.