Environmental Exposure and DNA Damage

我们的实验室对与暴露和癌症相关的遗传和表观遗传修饰广泛感兴趣。结直肠癌是世界上第四大最常见的癌症，食用红肉和加工肉与患这种癌症的风险和死亡率增加有关。特别是，食用含有高水平杂环胺（HCAs）的红肉和高温烹制的肉与结直肠腺瘤的风险增加有关。HCAs是一种致突变和致癌的化合物，通过高温烹调，特别是用平底锅煎炸，将肉类中的芳香氨基酸和肌酐热解形成。我们招募了16名健康志愿者参加为期4周的对照喂养研究，其中8名受试者被随机分配到含有低温（100℃）或高温（250℃）烹饪肉类的饮食方案中，每种方案在交叉设计中持续2周。另外8名受试者被随机分配到含有高温肉类饮食或与3种假定的诱变剂抑制剂（十字花科蔬菜、酸奶和叶绿素片）的饮食方案中，同样采用交叉设计。与低温肉日粮相比，高温肉日粮增加了尿液和粪便的致突变性。抑制剂饮食使目标结肠细胞的DNA损伤减少了近两倍。据我们所知，这是第一次证明饮食因素可以减少与油炸肉类相关的致癌作用的目标组织中的DNA损伤。

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. 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. 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. 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. 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. 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.