Mechanisms of FHIT Gene Fragility in Human Cancers Induced by Carcinogens

描述：(申请人描述)我们建议通过对涉及断裂的FHIT基因的整个区域进行测序，以及通过克隆和测序涉及肺癌、食道癌、胃肠道癌和宫颈癌的断裂点，来确定人类癌症中FHIT基因重排的机制。由于FHIT基因是由化学物质(如香烟烟雾中存在的苯并苯)或生物制剂(如人类乳头瘤病毒)引起的肿瘤重排的靶点，我们将比较肺癌和宫颈癌中的断点序列，以确定断点是涉及相同区域还是不同区域，以及这些肿瘤的断点两侧是否存在相同或不同的重复元件。如果我们确定肺癌的断裂点聚集在FHIT基因的离散区域内，我们将比较40岁之前患肺癌的吸烟者和没有患肺癌的吸烟百岁老人的这些区域的DNA序列。这项研究可能为FHIT基因在癌症易感性中的作用提供重要信息。同时，我们将确定人类NIT基因和肿瘤基因座的序列和结构，以及项目1分离的FHIT相互作用基因座的序列。

DESCRIPTION: (Applicant's Description) We propose to determine the mechanisms of FHIT gene rearrangements in human cancers by sequencing the entire region of the FHIT gene involved in the breaks and by cloning and sequencing breakpoints involved in lung, esophageal, gastrointestinal and cervical cancer. Since the FHIT gene is the target for rearrangements in tumors induced by either chemicals such as benzopyrene present in cigarette smoke or biological agents, such as human papillomaviruses, we will compare the sequences of breakpoints in lung cancer and cervical cancers to establish whether the breakpoints involve the same regions or different regions and whether the same or different repetitive elements flank the breakpoints in these tumors. If we establish that the breakpoints in lung cancer cluster within discrete regions of the FHIT gene we will compare the DNA sequence of these regions in smokers that have developed lung cancer before the age of forty and in smoking centenarians who have not developed lung cancer. This investigation could provide important information on the role of the FHIT gene in cancer predisposition. In parallel, we will determine the sequence and structure of the human NIT gene and locus in tumors, and sequence FHIT interacting gene loci isolated by Project 1.