BIOMARKERS OF CARCINOGENESIS

已知致癌作用涉及体细胞突变的多个步骤。在过去的二十年中，已经开发了各种生物标志物来检测人类致癌暴露的早期染色体和突变效应。虽然这些生物标志物已被证明与广泛的致癌暴露相关，但它们不是真正的早期效应生物标志物，因为它们不是环境诱导的癌症的因果途径。这些生物标志物应该是比目前可用的更好的癌症风险增加的预测因子。已知特定的染色体重排和改变的基因甲基化是白血病、淋巴瘤、肺癌和膀胱癌发展的关键因素。我们计划开发新的定量真实的时间PCR方法用于白血病/淋巴瘤相关易位（例如1（12;21）和t（14;18））和甲基化特异性PCR方法，使我们能够检查各种癌症相关基因（例如p16/INK 4a和p14/ARF）的甲基化状态。然后，我们将对这些标志物中的一些与非霍奇金淋巴瘤的关联进行初步测试，并检查它们在一般人群（包括新生儿）中的患病率。目前有相当大的争论存在易位在人类血液中，特别是在新生儿。此外，我们将进行体外细胞培养研究与这些新的标记物，以检查染色体损伤和异常基因甲基化的性质产生的关键靶细胞的超级基金化学品，砷和苯。我们还计划使用实时PCR方法从项目2下收集的儿童白血病病例的新生儿血液样本中回溯白血病至出生。这将确定白血病病例血液中存在的易位或倒位是否在出生时就存在，并为潜在预测儿童白血病开辟新的途径。最后，我们将甲基化特异性PCR方法应用于项目2收集的白血病骨髓样本和项目3收集的砷流行区肺和膀胱肿瘤中的特定基因，以确定肿瘤中是否存在化学特异性基因甲基化模式。

Carcinogenesis is known to involve multiple steps of somatic mutation. During the last two decades various biomarkers have been developed to detect early chromosomal and mutational effects of carcinogenic exposure in humans. Although these biomarkers have been shown to be associated with a wide range of carcinogenic exposures, they are not truly biomarkers of early effect as they are not on the causal pathway of environmentally-induced cancers. These biomarkers should be better predictors of increased cancer risk than those currently available. Specific chromosome rearrangements and altered gene methylation are known to be key factors in the development of leukemia, lymphoma, lung and bladder cancer. We plan to develop novel quantitative real time PCR methods for a number of leukemia/lymphoma-related translocations (e.g. 1 (12;21) and t(14;18)) and methylation-specific PCR methods that allow us to examine the methylation status of various cancer-related genes (e.g.p16/INK4a and p14/ARF. We will then make an initial test of the association of some of these markers with non-Hodgkins lymphoma and examine their prevalence in the general population, including newborns. There is currently considerable debate about the presence of translocations in human blood, especially in newborns. In addition, we will perform in vitro cell culture studies with these new markers to examine the nature of the chromosomal damage and aberrant gene methylation produced in critical target cells by the Superfund chemicals, arsenic and benzene. We also plan to use the real-time PCR methods to backtrack leukemia to birth in newborn blood samples from childhood leukemia cases collected under Project 2. This will determine if the translocations or inversions present in the blood of leukemia cases were present at birth and open up new avenues for potentially predicting childhood leukemia. Finally, we will apply the methylation specific-PCR methods to specific genes in leukemia marrow samples collected under Project 2 and in lung and bladder tumors from arsenic endemic areas collected under Project 3, to determine if chemical-specific gene methylation patterns exist in the tumors.