METABOLIC GENOTYPES & ONCOGENIC DAMAGE IN BREAST CANCER

环境和遗传因素之间的相互作用已被认为与乳腺癌的病因学有关。特别是，几项研究表明，在人类乳腺肿瘤中观察到的遗传损伤类型可能会受到化学毒物暴露的影响。然而，很少有人尝试将乳腺组织代谢化学致癌物的能力与在关键致癌基因上观察到的突变类型进行比较。为了更好地了解乳腺癌的病因，并确定基因/环境相互作用在确定个体乳腺癌形成易感性中的作用，将利用前瞻性的病例-病例研究设计，比较P53基因突变和受影响的癌症患者4种代谢酶(CYP1A1、GSTM、GSTT和GSTP)的基因突变，这些酶在人类环境致癌物的新陈代谢中起关键作用。我们假设，那些含有特定等位基因的乳腺癌患者，无论是含有增强环境毒物代谢活性的特定等位基因，还是含有可导致较少解毒的GSTs基因类型，都更有可能在P53基因座上发生累积的遗传损伤，并且增加反应性亲电体负担的等位基因组合将更容易引发肿瘤。肿瘤组织样本将通过SSCP和基因测序分析P53的基因变化。从血液中获得的DNA将通过PCR-RFLP进行基因分型，以确定P53基因受损的患者是否更频繁地表现出增加环境毒物形成反应性亲电的代谢基因型。前瞻性研究设计将允许使用问卷来确定其他潜在因素(包括吸烟、饮食、职业、种族和生育史)，这些因素可能会改变P53基因和突变之间的关联。由于P53基因突变与患者预后不良有关，这些研究将有助于识别在乳腺癌发病机制中发挥作用的关键调控基因受损的风险，并将进一步了解乳腺癌的病因和危险因素。

Interactions between environmental and genetic factors have been implicated in the etiology of breast cancer. In particular, several studies have suggested that the type of genetic damage observed in human breast tumors may be influenced by exposure to chemical toxicants. However, few attempts have been made to compare the ability of breast tissue to metabolize chemical carcinogens with the types of mutations observed at critical oncogenic loci. To better understand the etiology of breast carcinogenesis and determine the role of gene/environmental interactions in determining individual susceptibility to breast cancer formation, a prospective case-case study design will be utilized to compare mutations in the p53 gene with the genotype of affected cancer patients for 4 metabolic enzymes (CYP1A1, GSTM, GSTT, and GSTP) that play key roles in the metabolism of human environmental carcinogens. We hypothesize that those breast cancer patients containing either specific alleles of CYP1A1 that enhance the metabolic activation of environmental toxicants or genotypes of GSTs that would result in less detoxification will be more likely to have accrued genetic damage at the p53 locus, and that combinations of alleles that increase the burden of reactive electrophiles will be more susceptible to tumor initiation. Tumor tissue samples will be analyzed for genetic alterations in p53 by SSCP and gene sequencing analyses. DNA obtained from blood will be genotyped by PCR-RFLP to determine if patients harboring genetic damage to p53 more frequently exhibit metabolic genotypes that increase formation of reactive electrophiles from invironmental toxicants. A prospective study design will allow use of a questionnaire to identify other potential factors (including smoking, diet, occupation, race, and reproductive history) that may modify the association between genotype and mutations to p53. As mutation at p53 has been implicated in poor patient prognosis, these studies should aid in identifying those patients at risk for damage to key regulatory genes that play a role in the pathogenesis of breast cancer, and will further our understanding of the etiology and risk factors for this disease.