No abstract

Sufficient epidemiologic evidence has established an etiologic link between bladder cancer risk and occupational exposure as a painter to organic solvents. Currently, it remains to be established whether gene-specific promoter methylation contributes to bladder cancer development, including by enhancing chromosome breakage or loss. We investigated the effect of chronic exposure to organic solvents and paints on DNA methylation profiles in the promoter regions of four genes (GSTP1, p16(INK4a), APC and CDH1) and micronucleus (MN) frequency in exfoliated urothelial cells from voided urine from Colombian male non-smoking car painters and age-matched unexposed individuals. The exposed group had a higher percentage of individuals with >2 MNs/2000 cells compared with the unexposed group (P=0.04). Gene-specific analysis showed a significantly higher percentage of individuals with methylated GSTP1, p16(INK4a) and APC in the exposed group. Poisson regression analysis indicated that exposed individuals with methylated GSTP1 and p16(INK4a) promoters were more than twofold more likely to have an increase in MN frequency as compared with the reference. Finally, among exposed individuals with GSTP1 and p16(INK4a) methylated promoters, those with a greater age had a higher RR of increased MN frequency compared with younger exposed individuals with methylated promoters. These results support the conclusion that gene-specific promoter methylation may increase MN frequency in a dependent or independent interaction with occupational exposure to organic solvents.

Bladder cancer is the 9th most common cancer worldwide and patients often receive late diagnosis. Due to its high recurrence (50-80%) this malignancy is the fifth most expensive cancer in terms of total medical care expenditures. Even though epidemiologic evidence shows the etiologic link between occupational exposure to organic solvents and bladder cancer, not all exposed individuals develop such disease, making it an attractive target for prevention and risk stratification. Previously, we reported the association between multiple polymorphisms in DNA-repair and metabolism genes and an increase in chromosome instability in workers exposed to organic solvents; however, it is still unclear whether gene-specific promoter methylation contributes to chromosome breakage or loss, as an intermediate end point of disease. Here, we investigated the effect of chronic exposure to organic solvents and paints on DNA-methylation profiles and micronuclei frequency in non-smoking, car painter compared to age matched referents (non-exposed). Micronucleus frequency and methylation profiles in gene promoters of E-cadherin (CDH-1), p16INK4a, Glutathione S-transferase P (GSTP1), and Adenomatous polyposis coli (APC), were assessed in exfoliated urothelial cells from voided urine. Poisson regression analysis indicated a significant increase in micronuclei frequency in all individuals with CDH-1- (RR 16.91, 95% CI 8.2-35.76, p< 0.001) and GSTP1- (RR 2.23, 95% CI 1.58-3.12, p< 0.001) promoter methylation. In addition, exposed workers with methylated p16INK4a promoter had an increased micronuclei frequency in relation to the matched referents (RR 1.93, 95% CI 1.45-2.55, p< 0.001). In contrast, methylation in the APC promoter was associated with decreased micronuclei frequency in all individuals (RR 0.11, 95% CI 0.7-0.19, p< 0.001). Finally, overall the exposed group had a higher percentage of individuals with > 2 micronuclei/2000 cells compared to the referent group (p = 0.04). These results support the conclusion that gene-specific promoter methylation may increase micronuclei frequency in a dependent or independent interaction with occupational exposure to organic solvents. The present and other studies might be used in the primary prevention of bladder cancer to encourage preventive measures at the work place and lifestyle changes in those at highest risk of developing the disease. Citation Format: Luz S. Hoyos-Giraldo, Luisa F. Escobar-Hoyos, Diana Saavedra-Trujillo, Ingrid Reyes-Carvajal, Adriana Muñoz, Elizabeth Londoño-Velasco, Angela Tello, Silvio Carvajal, Regina Santella. Gene-specific promoter methylation is related to micronuclei frequency in urothelial cells from individuals exposed to organic solvents and paints. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 830. doi:10.1158/1538-7445.AM2015-830