Superfund Research Program

Arsenic Mode of Action in Cancer: Models of Epigenetic Mechanism

Project Leader: Karl T. Kelsey
Grant Number: P42ES005947
Funding Period: 2000 - 2006

Project-Specific Links

Final Progress Reports

Year:   2005 

This work is being done in collaboration with Dr. Margaret Karagas, a co-investigator from the Superfund Basic Research Program at Dartmouth University.  Dr. Karagas has obtained paraffin blocks and lymphocyte DNA on more than 400 bladder cancer patients (with additional peripheral blood obtained from over 400 population-based controls) that have been enrolled in the now ended phase of her NIEHS Superfund funded study of bladder cancer and arsenic exposure in New Hampshire.  These blocks have been utilized to prepare slides and DNA for study.  These sections have been stained for p53 protein and have been used for DNA extraction in Dr. Kelsey’s laboratory at the Harvard School of Public Health.

The work completed to date will allow us to analyze whether or not environmental exposure to arsenic, primarily from drinking water, is associated with any particular type of somatic alterations in bladder tumors from the study participants.  This is critically important, as it will allow us to determine if this pathway toward bladder carcinogenesis is specific for this exposure.

The work will also further define the role of growth stimulatory genes DNA in susceptibility to this disease.   To date, Dr. Kelsey’s laboratory has completed analysis of promoter methylation at approximately 20 tumor suppressor loci.  They have studied the relationships with arsenic exposure and published their recent finding that epigenetic silencing of the trypsinogen gene locus and the RASSF1A locus is more prevalent in patients with bladder cancer who have a history of higher exposure to arsenic, measured as toenail concentrations.  The researchers continue to construct patterns of other somatic alterations (including p53 alteration, 3p deletion and MDM2 amplification as well as cyclin D amplification), determining whether there exist specific “fingerprints” for genomic alteration in tumors from arsenic exposed individuals.