RESUMEN
BACKGROUND: Previous studies have demonstrated that ingestion of arsenic in drinking water is a strong risk factor for several forms of cancer, including bladder cancer. It is not known whether arsenic-related cancers are genetically similar to cancers in unexposed individuals or what mechanisms of carcinogenesis may underlie their formation. This study was designed to compare chromosomal alterations in bladder cancers of arsenic-exposed individuals to provide insight into the mechanism of how arsenic may induce or promote cancer. METHODS: A case-case study was conducted in Argentina and Chile examining chromosomal alterations in bladder tumor DNA in 123 patients who had been exposed to arsenic in their drinking water. Patients were placed into one of four arsenic exposure categories according to their average 5-year peak arsenic exposure. Patients were also classified as ever smokers or never smokers. Comparative genomic hybridization was used to identify chromosomal alterations throughout the genome. All statistical tests were two-sided. RESULTS: The total number of chromosomal alterations was higher in individuals exposed to higher arsenic levels (5.7 +/- 5.1, 5.6 +/- 5.1, 7.3 +/- 7.4, and 9.1 +/- 6.5 [mean +/- standard deviation] chromosomal alterations per tumor with increasing arsenic exposure; P(trend) =.02, adjusted for stage and grade). The trend was stronger in high-grade (G2-G3) tumors (6.3 +/- 5.5, 8.3 +/- 4.7, 10.3 +/- 7.8, and 10.5 +/- 6.4 alterations per tumor; P(trend) =.01) than it was in low-grade (G1) tumors (3.5 +/- 3.1, 1.1 +/- 1.1, 2.5 +/- 2.5, and 3.6 +/- 3.2 alterations per tumor; P(trend) =.79). The mean number of chromosomal alterations also increased with tumor stage and grade (P(trend)<.001) independently of arsenic exposure but was not associated with smoking history. Deletion of part or all of chromosome 17p (P(trend)<.001) showed the strongest association with arsenic exposure. CONCLUSIONS: Bladder tumors in patients with higher levels of arsenic exposure showed higher levels of chromosomal instability. Most of the chromosomal alterations associated with arsenic exposure were also associated with tumor stage and grade, raising the possibility that bladder tumors from arsenic-exposed patients may behave more aggressively than tumors from unexposed patients.