) Our objective is to utilize genomic sequencing and analysis to identify candidate tumor suppressors that we presume reside within regions that we have found are homozygously deleted in human cancers. We shall: a) determine the complete and accurate nucleotide sequence of the chromosomal regions found to be repeatedly deleted in human cancers, with a special emphasis on breast cancer; b) use sequence analysis and data base searching to find candidate genes from these regions; c) determine the complete intron/exon structures for the validated tumor suppressor genes transcribed from these regions. Sequencing of two regions is currently in progress: the region on chromosome 10 that harbors PTEN, a tumor suppressor gene that is frequently mutated in advanced breast, brain and prostate cancers; and a region on chromosome 20 that is frequently deleted in gastrointestinal tumors. Multiple loci are in the process of characterization, including two sites on chromosome eight, one on 21, and one on 4 that are deleted in a variety of cancers. We expect to be sequencing and analyzing about 5 loci per year, each about 300-400 kb in length. This work will complement other work in progress at the Cold Spring Harbor Cancer Center that utilizes RDA (representational difference analysis) to identify deleted loci, uses methods of exon trapping and hybrid selection to identify candidate genes from these loci, and uses mutational analysis to validate the involvement of candidate genes in clinical cancer.
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