Hypermethylation of genes detected in urine from Ghanaian adults with bladder pathology associated with Schistosoma haematobium infection.

PLoS One. 2013;8(3):e59089.

Zhong X, Isharwal S, Naples JM, Shiff C, Veltri RW, Shao C, Bosompem KM, Sidransky D, Hoque MO.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.




Schistosoma haematobium is associated with chronic bladder damage and may subsequently induce bladder cancer in humans, thus posing a serious threat where the parasite is endemic. Here we evaluated aberrant promoter DNA methylation as a potential biomarker to detect severe bladder damage that is associated with schistosomiasis by analyzing urine specimens.


A quantitative methylation-specific PCR (QMSP) assay was used to examine the methylation status of seven genes (RASSF1A, RARβ2, RUNX3, TIMP3, MGMT, P16, ARF) in 57 urine samples obtained from volunteers that include infected and uninfected by S. haematobium from an endemic region. The Fishers Exact Test and Logistic Regression analysis were used to evaluate the methylation status with bladder damage (as assessed by ultrasound examination) in subjects with S. haematobium infection.


RASSF1A and TIMP3 were significant to predict severe bladder damage both in univariate (p = 0.015 and 0.023 respectively) and in multivariate (p = 0.022 and 0.032 respectively) logistic regression analysis. Area under the receiver operator characteristic curves (AUC-ROC) for RASSF1A and TIMP3 to predict severe bladder damage were 67.84% and 63.73% respectively. The combined model, which used both RASSF1A and TIMP3 promoter methylation, resulted in significant increase in AUC-ROC compared to that of TIMP3 (77.55% vs. 63.73%.29; p = 0.023).


In this pilot study, we showed that aberrant promoter methylation of RASSF1A and TIMP3 are present in urine sediments of patients with severe bladder damage associated with S. haematobium infection and that may be used to develop non-invasive biomarker of S. haematobium exposure and early molecular risk assessmentof neoplastic transformation.

PMID: 23527093



Our work with Schistosoma haematobium and bladder cancer has been inspired by the unknown impact of this infection on public health in endemic areas.  In the past, most of the pathological evidence has come from Egypt, and there has been excellent research done in this area, but still most health systems consider the infection to be benign. It is known that schistosome-associated bladder cancer involves squamous cell carcinoma, and this form of bladder of bladder cancer is associated with chronic inflammation.  Importantly it is seen in adults, whereas most importance is directed to children assuming  adult patients have some immunity, yet this is not the case.  We have shown in Ghana that this parasite is dangerous, and that chronic effects can be seen in a high proportion of adult rural populations residing in endemic areas.  Now we have demonstrated a genetic basis associated with inflammation in people with chronic schistosome infections.  We hope that this information will be picked up by others particularly those research workers interested in bladder cancer because it is clear from our work that this condition is much more common in areas where Schistosoma haematobium is prevalent than previously assumed, and this may contribute to mortality at an unknown but significant rate.

Clive Shiff-1

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