Lee Moore, Ph.D., M.P.H.
|Organization:||National Cancer InstituteDivision of Cancer Epidemiology & Genetics, Occupational and Environmental Epidemiology Branch|
|Address:||Executive Plaza SouthRoom 8102|
Dr. Moore received a Ph.D. in environmental health science and an M.P.H. in industrial hygiene from the University of California at Berkeley. She completed post-doctoral studies at the University of California San Francisco's Cancer Center and joined the NCI as a tenure-track investigator in the Occupational and Environmental Epidemiology Branch in 2001.
Use of molecular markers to measure the biological effects of carcinogens in human tissues. Molecular epidemiology of environmental arsenic exposure and of bladder and renal cell carcinoma.
We are investigating the role of various markers to measure the biological effects of carcinogens in human tissues. We use early biomarkers of effect such as the micronucleus assay and fluorescent in situ hybridization in human lymphocytes and exfoliated cells to look for exposure- dependent increases in genetic damage and aneuploidy in exposed individuals. We also use DNA to examine whether individuals carrying variant genotypes or polymorphisms of metabolism genes may be more susceptible to environmental carcinogens and thus more susceptible to cancer than those carrying wild-type copies of the same genes. More recently with the genomics revolution, this work has expanded to examine tumor tissues, DNA, and RNA using methods such as comparative genomic hybridization, immunohistochemistry, and arrays to determine how exposed tumors are different from unexposed tumors in the genetic changes they carry and the genes and proteins they express.
Inorganic arsenic is considered one of the highest priority public health concerns, particularly because of its clear carcinogenic potential. The study of arsenic has worldwide and national importance since millions of people are currently exposed to low levels of naturally occurring arsenic in their drinking water. Arsenic is also considered the number one priority carcinogen by the Agency for Toxic Substance and Disease Registry, and currently the Environmental Protection Agency is considering a new maximum contaminant level for arsenic in drinking water. Although arsenic is an established human carcinogen that has been well-studied in past years, the mechanism and dose at which it causes cancer are still unclear. Genetic studies comparing tumors from exposed and unexposed individuals can provide insight into the mechanism of chemically-induced cancers. We conducted a case-case study comparing high and low arsenic-exposed tumors from Argentina and Chile. We used comparative genomic hybridization to define genetic aberrations throughout the genome, p53 mutational spectrum analysis, and immunohistochmistry to determine to determine if exposed and unexposed tumors were different. It was found that bladder tumors associated with higher levels of arsenic exposure showed increased chromosomal instability, and that most of the specific chromosome changes associated with arsenic exposure were also associated with tumor stage and grade, suggesting that arsenic-exposed tumors may behave more aggressively resulting in increased bladder cancer mortality. We also used p53 mutational spectrum analysis to determine if the frequency, type, and location of p53 mutations in exposed and unexposed tumors were different. Although the overall frequency of mutations was not different, we found that the type of mutations was different in exposed and unexposed tumors. While tumors associated with tobacco smoke contained more G to A transitions at CpG sites, arsenic-exposed tumors demonstrated an increase in the frequency of transversions at only nonCpG sites.
We are also examining variations in arsenic susceptibility using blood measurements of micronutrients, phenotypic markers of arsenic methylation and detoxification, and genetic markers of susceptibility in populations of India and South America. Evidence of a genetic contribution to methylation-mediated detoxification patterns was investigated in families using urinary methylation as a phenotypic marker of metabolism. There are plans to extend arsenic studies to include exposed regions in Inner Mongolia and New England.
Renal cell carcinoma has several known risk factors including obesity, hypertension, and cigarette smoking. TCE and other organic solvents are suspected carcinogens. Enzymes that biotransform carcinogens have high levels of activity in the kidney yet polymorphisms in genes that encode for these enzymes have received little study. Similarly, the relationship between genes involved in obesity, hypertension and renal cancer have not been examined. We are currently investigating whether the presence of polymorphisms in metabolism, hypertension, and obesity genes may increase renal cell cancer risk in patients enrolled in a multi-center Eastern European kidney cancer study. We are examining the von Hippel-Lindau (VHL) gene in tumor DNA from cases for exposure-specific inactivation via mutation and methylation. We also plan to conduct expression array analyses using RNA from a subset of cases to determine if environmental or host factors modify gene expression in renal tumors.