METABOLIC GENOTYPES & ONCOGENIC DAMAGE IN BREAST CANCER

环境和遗传因素之间的相互作用与乳腺癌的病因有关。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受到接触化学毒物的影响。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位点观察到的突变类型进行比较。为了更好地了解乳腺癌发生的病因，确定基因/环境相互作用在决定个体乳腺癌形成易感性中的作用，我们将采用前瞻性个案研究设计，比较在人类环境致癌物代谢中起关键作用的4种代谢酶（CYP1A1、GSTM、GSTT和GSTP）的p53基因突变与受影响癌症患者的基因型。我们假设，那些乳腺癌患者含有CYP1A1的特定等位基因，增强环境毒物的代谢激活，或gst的基因型，导致较少的解毒，将更有可能在p53位点积累遗传损伤，并且增加活性亲电试剂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和基因测序分析来分析p53基因的改变。从血液中获得的DNA将通过PCR-RFLP进行基因分型，以确定携带p53基因损伤的患者是否更频繁地表现出代谢基因型，从而增加环境毒物中反应性亲电试剂的形成。前瞻性研究设计将允许使用问卷来确定其他可能改变基因型和p53突变之间关系的潜在因素（包括吸烟、饮食、职业、种族和生殖史）。由于p53突变与患者预后不良有关，这些研究应有助于识别那些在乳腺癌发病机制中起作用的关键调控基因受损的患者，并将进一步了解该疾病的病因和危险因素。

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.