IDENTIFICATION OF 3P RECESSIVE ONCOGENES IN LUNG CANCER

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Recessive oncogenes (tumor suppressor genes, TSGs) play a major role in the pathogenesis of human lung cancel Currently, chromosome region 3p is the most frequently involved site exhibiting allele loss in lung cancer suggesting the location of one or more new TSGs. Allelotyping evidence suggests several 3p distinct putative TSGs sites located at 3p25 (VHL and others), 3p2l .3 (two sites), 3pl4.2 (FHIT/FRA3B), and 3pl2-l3. Studies of preneoplasia indicate the loss of 3p alleles is the earliest alteration known in preneoplastic lesions and even some histologically normal epithelium of smokers. The timing suggests one or more 3p recessive oncogenes function as "gatekeepers" in the molecular pathogenesis of lung cancer. We want to identify all of these genes and translate this information into the clinic to aid in early diagnosis, monitoring of chemoprevention, and potentially as a base for developing new therapies. The specific aims of this project are: (l) isolate a new lung cancer related TSG(s) in the lung cancer 3p2l .3 homozygous deletion region and to test for mutations in candidate genes in lung cancer and preneoplastic lesions; (2) test if the growth properties of lung cancer cell lines suggesting malignancy are altered following the introduction of specific candidate 3p TSGs as well as portions of chromosome 3p; and (3) test if telomerase activity can be repressed in lung cancer cells following the introduction specific candidate 3p TSGs as well as portions of chromosome 3p. The ultimate translational goals are to apply this information to develop new methods for identification of genetic changes in preneoplastic lesions for very early lung cancer diagnosis; use as surrogate molecular markers in chemoprevention trials; search for genetic predisposition via germline mutations in the gene; and potentially to develop tumor specific therapy. Thus, this project interacts with Project #2 (Genetic Susceptibility to Lung Cancer), Project #3 (Molecular early Detection of Lung Cancer) and Project #4 (Chemoprevention of Lung Cancer). We have made substantial progress on all of the aims particularly the discovery of multiple genes with some mutations, several genes with growth suppressing and apoptotic inducing activity, #3 microcell hybrids with growth suppression, and the discovery of multiple breakpoints in the region in cancers, preneoplastic lesions, and normal epithelium. These precise 3p21 .3 breakpoints are the same as those seen as risk factors in BPDE treated lymphocytes of lung cancer patients and thus provide a tie between target and peripheral tissues.