Environmental Exposure and DNA Damage

Our laboratory is broadly interested in both genetic and epigenetic modifications associated with exposure and cancer. Colorectal cancer is the fourth most common cancer worldwide, and consumption of red and processed meat has been associated with increased risk of and mortality from this cancer. In particular, consumption of red meat and meat cooked at high temperature containing elevated levels of heterocyclic amines (HCAs) is associated with increased risk of colorectal adenoma. HCAs are mutagenic and carcinogenic compounds formed through pyrolysis of aromatic amino acids and creatinine in meats cooked at high temperature, particularly by pan-frying. <P> We enrolled 16 healthy volunteers in a 4-week controlled feeding study where 8 subjects were randomly assigned to dietary regimens containing meat cooked at either low (100C) or high temperature (250C), each for 2 weeks in a crossover design. The other 8 subjects were randomly assigned to dietary regimens containing the high-temperature meat diet alone or in combination with 3 putative mutagen inhibitors: cruciferous vegetables, yogurt, and chlorophyllin tablets, also in a crossover design. The high-temperature meat diet increased the mutagenicity of urine and feces compared to the low-temperature meat diet. The inhibitor diet decreased nearly twofold the DNA damage in target colorectal cells. To our knowledge, this is the first demonstration that dietary factors can reduce DNA damage in the target tissue of fried-meat associated carcinogenesis. Breast cancer is one of the most common cancers in women, yet even with a stabilizing incidence rate and decreased mortality, more than 180,000 women will be diagnosed and more than 40,000 women will die in the U.S. from the disease this year. <P> Recent genome-wide association studies have identified several polymorphisms associated with breast cancer although risks from these polymorphisms are modest. Our group is testing the hypothesis that certain DNA modifications are associated with breast cancer risk. Such modifications may be determined by both environmental and genetic factors, and would be expected to change over a woman's lifetime. Telomeres are non-coding double-stranded repeats located at ends of chromosomes that play a critical role in maintaining genomic integrity. Experimental studies indicate that telomere dysfunction may be an important cause of chromosomal abnormalities in breast epithelium. Studies have demonstrated progressively shorter telomere length with increasing chromosomal aberrations in breast carcinomas. However, epidemiologic studies examining the association between leukocyte telomere length and breast cancer have yielded equivocal results. <P> We examined telomere length in peripheral blood in relation to breast cancer risk in a prospective cohort study of women who have at least one sister with breast cancer. We compared 342 women with incident breast cancer to a set of 735 women without cancer sampled from the Sister Study cohort and measured relative telomere length in peripheral blood using single tube monochrome multiplex quantitative PCR. We found no evidence of increased risk associated with shortened telomeres.Epigenetic modifications, including DNA methylation, are being increasingly recognized as is being recognized as important determinants of gene transcriptional regulation that have both heritable and acquired characteristics. Aberrant DNA methylation patterns are among the earliest and most common events in carcinogenesis and recent studies suggest that the epigenetic profile of DNA from a surrogate tissue, peripheral blood, may differ between women with active ovarian cancer compared to women without disease. <P> We have employed genome-wide profiling of DNA methylation in peripheral blood samples from more than 900 women in order to investigate whether the pattern of DNA methylation is associated with breast cancer risk. We have identified a number of methylation sites that are associated with increased risk and are continuing data analysis.A second form of epigenetic modification is miRNA expression. Altered miRNA expression is a central feature of cancer and miRNA expression signatures have been shown to be associated with diagnosis, stage, prognosis, and response to treatment. Expression patterns for cancer show high tissue specificity making them potential markers for cancer screening. Breast cancer specific miRNAs have been shown to correlate with stage, vascular invasion, proliferative index, and ER/PR status. <P> Recently, sufficient levels of miRNAs have been found in human plasma and serum to permit profiling, with sufficient power to distinguish men with metastatic prostate cancer from men without cancer and women with ovarian cancer. We have recently completed assays on more than 400 serum samples from cases and non-cases using the Sister Study cohort and are in the process of data analysis.