) 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.
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