Mechanisms of FHIT Gene Fragility in Human Cancers Induced by Carcinogens

致癌物诱发人类癌症中FHIT基因脆性的机制

• 批准号: 6313441
• 负责人: CARLO M CROCE
• 金额: $ 15.13万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6313441
• 关键词: cell line; cervix neoplasms; chemical carcinogen; chemical carcinogenesis; disease /disorder etiology; environment related neoplasm /cancer; environmental toxicology; esophagus neoplasm; gastrointestinal neoplasms; gene deletion mutation; gene rearrangement; human genetic material tag; human tissue; lung neoplasms; molecular cloning; neoplasm /cancer genetics; nucleic acid repetitive sequence; smoking; tobacco abuse; tumor suppressor genes

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.

（申请人描述）我们建议通过测序FHIT基因的整个断裂区域，以及克隆和测序涉及肺癌、食管癌、胃肠道和宫颈癌的断裂点，来确定FHIT基因在人类癌症中的重排机制。由于FHIT基因是由化学物质（如香烟烟雾中的苯并芘）或生物制剂（如人类乳头瘤病毒）诱导的肿瘤中重排的靶标，我们将比较肺癌和宫颈癌的断点序列，以确定断点是否涉及相同区域或不同区域，以及这些肿瘤中的断点两侧是否有相同或不同的重复元件。如果我们确定肺癌的断点集中在FHIT基因的离散区域内，我们将比较40岁以前患肺癌的吸烟者和未患肺癌的百岁吸烟者的这些区域的DNA序列。这项研究可以为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基因和肿瘤位点的序列和结构，并对项目1分离的FHIT相互作用基因位点进行测序。