BERKELEY, CA (UroToday.com) - The present study confirms the carcinogenic nature of arsenic.
Moreover, the long latency observed is a major concern, since further cases should present during the next years. The latter considering that individuals exposed as children are progressively getting to an age where cancers are appearing. The implementation of screening programs and the identification of arsenic-related urothelial carcinogenesis mechanisms are probably the most relevant factors to overcome this situation.
Active screening for bladder cancer (BC) is not recommended by any major organization due to insufficient evidence supporting it.1 One of the most important arguments against its implementation is the low prevalence of the disease in the general population. Another relevant issue is the high cost and invasiveness (cystoscopy) of the diagnostic workup if testing is positive. Finally, the low sensitivity and specificity of available screening methodologies is also a problem. However, small studies testing haemoglobin chemical reagent strips have shown benefits in terms of tumoral stage at presentation and survival for screened men.2 Moreover, the use of urine-based markers has been shown to be cost-effective in a high-risk population (heavy smokers).3
Since risk factors for BC are well defined; trials should be focused on those groups. In order to further improve the efficiency of BC screening programs, some authors have proposed the use of urine-based markers as a secondary non-invasive screening tool.4 This would lead to fewer cystoscopies and reduced costs. The exposed population in Antofagasta, Chile fits perfectly in the mentioned category and a screening program would probably be the most important single measure to improve outcomes of this disease in this region.
Despite the significant impact of arsenic exposure on health, only a small proportion of these exposed subjects are affected. This suggests the existence of an individual susceptibility to arseniasis and its consequences, in particular malignant neoplasias.
Several mechanisms for arsenic-induced carcinogenesis have been studied,5,6 including genetic and epigenetic7 alterations, impairment of DNA-repair,8 oxidative stress, alterations in cell death and proliferation9 and aberrant activation of signal transduction pathways. However, the exact mechanism still remains unclear.
A number of studies have looked at different features potentially involved in carcinogenesis of arsenic-related urothelial cancer. A case-case study using comparative genomic hybridization in arsenic-exposed patients in Chile and Argentina showed higher levels of chromosomal instability in tumors from patients exposed to high levels of arsenic. Moreover, a significant association of chromosomal alterations with a higher tumor stage and grade was also observed.10 Similar studies have compared chromosomal imbalances between arsenic-related and non-arsenic related BC, showing a higher frequency among the former. In addition, loss of heterozygosity has also been reported as more frequent in arsenic-induced tumors than in those not related to arsenic exposure.11 Further studies have evaluated epigenetic phenomena related to BC in arsenic-exposed populations. Chen et al. demonstrated a significantly higher rate of death-associated protein kinase hypermethylation in BC patients from arsenic-contaminated areas, showing also an association with more aggressive tumoral features and less favorable clinical outcomes.12
In addition to the mentioned acquired genetic changes, constitutional genetic factors have also been recognized. Recently, Chung et al. were able to identify two single-nucleotide polymorphisms in arsenic-metabolizing enzymes, such as glutathione-S-transferase (GST), showing a significant relation with altered urinary arsenic profiles in patients with BC.13 However, further evaluation of GST polymorphic variants (GSTT1 and GSTM1) did not show a clear association with arsenic metabolite excretion levels in a healthy Chilean patients.14
In summary, the association of the mentioned chromosomal alterations and candidate genes polymorphisms with arsenic-related BC has to be further verified, making genetic studies in exposed populations necessary. This is the case for Antofagasta.
References:
- Moyer VA. Screening for bladder cancer. US Preventive Services Task Force Recommendation Statement. Ann Intern Med (2011); 155: 246
- Messing EM, Madbeb R, Young T et al. Long-term outcome of hematuria home screening for bladder cancer in men. Cancer (2006); 107: 2173
- Lotan Y, Svatek R, Sagalowsky R et al. Should we screen flor bladder cancer in a high risk population? A cost per life-year saved analysis. Cancer (2006); 107: 982
- Fradet Y. Screening for bladder cancer: the best opportunity to reduce mortality. Can Urol Assoc J (2009); 3 (Suppl 4): S180
- Simeonova PP, Wang S, Toriuma W et al. (2000). Arsenic mediates cell proliferation and gene expression in the bladder epithelium: Association with activating protein-1 transactivation. Cancer Res 60: 3445
- Huang C, Ke Q, Costa M et al. (2004). Molechular mechanisms of arsenic carcinogenesis. Moll Cell Biochem 255: 57
- Su PF, Hu YJ, Ho IC et al. (2006). Distinct gene expression profiles in inmortalizd human urothelial cells exposed to inorganic arseniteand its methylated trivalent metabolites. Environ Health Perspect 114: 394
- Andrew AS, Burgess JL, Meza MM et al. (2006). Arsenic exposure is associated with decreased DNA repair in vitro and in individuals exposed to drinking water arsenic. Environ Health Perspect 11: 1193
- Ai Z, Lu W, Ton S et al.l (2007). Arsenic trioxide-mediated growth inhibition in gallbladder carcinoma cellsvia down-regulation of Cyclin D1 transcription mediated by Sp I transcription factor. Biochem Biopys Res Commun 360: 684
- Moore LE, Smith AH, Eng C et al. (2002). Arsenic-related chromosomal alterations in bladder cancer. J Natl Cancer Inst, 94: 1688
- Chen CJ, Hsu LI, Wang CH et al. (2005). Biomarkers of exposure, effect and susceptibility of arsenic-induced health hazards in Taiwan. Toxicol Appl Pharmacol 206: 198
- Chen WT, Hung WC, Kang WYet al. (2007). Urothelial carcinomas arising in arsenic-contaminated areas are associted with hypermethylation of the gene promoter of the death-associated protein kinase. Histopathology 51: 785
- Chung CJ, Pu YS, Su CT et al. (2011). Gene polymorphisms of gluthatione S-transferase omega 1 and 2, urinary arsenic methylation profile and urothelial carcinoma. Sci Total Environ 409(1), 465
- Caceres DD, Werlinger F, Orellana M et al. (2010). Polymorphism of Glutathione S-Transferase (GST) variants and its effect on distribution of urinary arsenic species in people exposed to low inorganic arsenic in tap water: an exploratory study. Arch Environ Occup Health 65(3): 140
Written by:
Mario I. Fernandez, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.