BIOMARKERS OF CARCINOGENESIS

已知癌变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。尽管这些生物标志物已被证明与广泛的致癌暴露有关，但它们并不是真正的早期效应生物标志物，因为它们不在环境诱发癌症的因果途径上。与现有的生物标志物相比，这些生物标志物应该能更好地预测癌症风险的增加。已知特定的染色体重排和基因甲基化改变是白血病、淋巴瘤、肺癌和膀胱癌发展的关键因素。我们计划开发用于白血病/淋巴瘤相关易位的新型实时定量PCR方法（例如1（12;21）和t(14;18)）和甲基化特异性PCR方法，使我们能够检测各种癌症相关基因（例如p16/INK4a和p14/ARF）的甲基化状态。然后，我们将对其中一些标记物与非霍奇金淋巴瘤的关联进行初步测试，并检查其在普通人群（包括新生儿）中的患病率。目前关于人类血液中易位的存在有相当大的争论，特别是在新生儿中。此外，我们将使用这些新标记进行体外细胞培养研究，以检查超级基金化学物质砷和苯在关键靶细胞中产生的染色体损伤和异常基因甲基化的性质。我们还计划在项目2中收集的儿童白血病病例的新生儿血液样本中使用实时荧光定量PCR方法回溯白血病到出生。这将确定白血病患者血液中的易位或倒位是否在出生时就存在，并为预测儿童白血病开辟了新的途径。最后，我们将应用甲基化特异性pcr方法对项目2中收集的白血病骨髓样本和项目3中收集的砷流行地区的肺和膀胱肿瘤中的特定基因进行甲基化，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.