DNA methylation profiles in urothelial bladder cancer tissues and children with schistosomiasis from Eggua, Ogun State, Nigeria

Abstract

AbstractSquamous cell carcinoma has been attributed to chronic schistosomiasis and is the predominant type of bladder cancer in schistosomiasis endemic areas. The aim of this study was to assess early promoter DNA methylation in selected genes implicated in schistosomiasis-associated bladder cancer (SABC). A total of 161 urine samples were collected from school aged children in Eggua Community of Ogun State and examined by microscopy forSchistosoma haematobiumeggs. From this sample, a subset of 34(21.1%) urine samples positive forS. haematobiumeggs and 22 formalin fixed paraffin-embedded bladder cancer tissues obtained from the University College Hospital Ibadan, were subjected to DNA isolation and bisulfite DNA conversion. Quantitative methylation specific PCR was used to determine the methylation status ofAPC, RARβ2, RASSF1AandTIMP3in the samples. Methylation inAPC, RARβ2, RASSF1A and TIMP3was observed in 24(70.6%), 18(52.9%), 15(44.1%) and 8(23.5%) of the positive urine samples respectively and in 7(31.8%), 13(59.1%), 17(77.3%) and 8(36.4%) of bladder cancer tissues respectively.APC, RARβ2andRASSF1Awere 5-fold, 2-fold and 27-fold downregulated respectively in positive urine samples and 9-fold, 3-fold and 15-fold downregulated respectively in the bladder cancer tissues. The odds of promoter methylation inRARβ2(OR: 1.133) were likely even with light infection. Gene promoter DNA methylation in tumour suppressor genes was observed in schistosomiasis cases. Hence, DNA methylation may occur during activeSchistosoma haematobiumin children. This result may serve as an early non-invasive biomarker to detect and hint at the risk of developing SABC later in life.Author summarySchistosoma haematobiumcan survive in the host for more than 20 years, during which time it causes damage to the bladder tissues and sometimes with no symptoms. Immune response to the parasite infection is inflammatory and leads to several morbidities like anaemia, undernutrition, dysuria, and female genital sores and may result in malignant transformation (schistosomiasis-associated bladder cancer) which presents in later years. Children are more susceptible to schistosomiasis because of having a naive immune system, making them targets for these morbidities, and including the possibility of developing bladder cancer in later years. DNA methylation which is often the first step in malignant transformation is known to be induced by inflammation during chronic schistosomiasis. Hence, assessing DNA methylation can serve as a biomarker for predicting the risk of developing bladder cancer later in life. In this study, we have established that DNA methylation occurs during childhood schistosomiasis and represents the time when events leading up to malignant transformation may begin. We suggest that once there is a schistosomiasis infection, DNA methylation will occur and unless the disease is treated on time, the individual is at risk of malignant transformation later in life.