CpG island methylation in Schistosoma- and non-Schistosoma-associated bladder cancer

Abstract

Urothelial carcinomas (TCC) constitute the vast majority of bladder cancers in most of the world. On the other hand, squamous cell bladder carcinoma, a rare subtype in the Western world, is a common subtype in areas with endemic Schistosoma infection. Although schistosomal infection has been reported to influence DNA methylation, the pattern and extent of CpG island hypermethylation in squamous cell carcinomas remain unknown. In this study, we used methylation-specific PCR to characterize 12 cancer-related genes in 41 bladder cancer samples from Egypt (31 squamous cell carcinomas (SCC), 21 of them associated with Schistosoma and 10 TCC, five of which were Schistosoma-associated). The genes analyzed included E-cadherin, DAP-Kinase, O6MGMT, p14, p15, p16, FHIT, APC, RASSF1A, GSTP1, RARbeta and p73. Methylation of at least one gene was detected in all squamous cell tumors except two, and 45% of samples had at least three methylated genes. The average methylation index was 0.24, corresponding to three of the 12 analyzed genes. Schistosoma-associated tumors had more genes methylated than non-Schistosoma tumors (average MI: 0.29 vs 0.14) (P = 0.027). Although the extent of methylation in TCC (average MI: 0.16) was lower than in squamous cell carcinomas (SCC), the overall profile of methylation was similar, with Schistosoma-associated cases having a higher methylation index. Our results suggest that schistosomal involvement associates with a greater degree of epigenetic changes in the bladder epithelium.

Prospects for Epigenetic Epidemiology

“…Insulin-like growth factor 2 methylation imprinting profile in the placenta is altered in mice infected with Campylobacter rectus during pregnancy (142). Similar alterations in DNA methylation have been reported in human cells and cell lines following viral or helminth infection (146)(147)(148)(149)(150)(151)(152). Methylation may be increased or decreased depending on the infectious agent (142,153).…”

Elevated oxidative stress and DNA damage and repair levels in urinary bladder carcinomas associated with schistosomiasis

“…52 Schistosomal infection may also influence DNA methylation. It was shown that Schistosoma-associated urinary bladder tumors had more genes methylated than non-Schistosomal tumors, 53 and the extent of methylation in UCs was lower than in SCCs. Also previous reports showed the presence of O 6 -methylguanine in the urinary bladder DNA from cancer patients with Schistosomiasis.…”

Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells

“…31,32 P16INK4A initiates cell cycle arrest by inhibiting cyclin-dependent kinase 4 (CDK4) during induced cell stress, for example, by chronic infection. Indeed, methylation-mediated silencing of several of these genes has been implicated in Schistosoma-associated bladder carcinoma 23 and in gastric H. pylori infection mentioned above. [24][25][26] Promoter methylation is also a common mechanism for downregulation of MLH1 and MGMT, two members of the DNA repair system.…”

“…22 Increased DNA methylation (hypermethylation) is often associated with loss of gene expression, although this paradigm has recently been challenged by the observation that expression of a significant number of genes is downregulated in Dnmt-deficient cells. Nevertheless, methylationassociated downregulation of genes can be seen in host cells in response to viral, parasitic and bacterial infections, including Schistosoma infection of the bladder 23 and Helicobacter pylori or Epstein-Barr virus infection of the stomach. [24][25][26][27] Human papillomavirus E7 and adenovirus E1A proteins have also been shown to directly associate with DNMT1 and stimulate DNMT1 activity.…”