Human breast carcinoma and human prostate carcinoma is thought to develop through progressive stages from atypical hyperplasia to in situ carcinoma and finally to invasive and metastatic cancer. The overall goal of the present studies are to employ a new microscopic sampling method to identify genes associated with LOH (loss of heterozygosity) which exhibit a common allelic change in both premalignant and invasive human carcinoma cells. The working hypothesis is that somatic genetic progression is driven by mutations in suppressor genes. A mutation in one allele is elevated to a dominant phenotype by LOH on the other allele. Under the step-wise progression from in situ to invasive cancer, a series of specific LOH and amplification lesions accumulate in the genome of the target epithelial cell. Investigating this hypothesis, employing the new microsampling method, we have identified a novel LOH loci on 11q13 in 50% sporadic breast cancer, with retention of the identical allele loss for concomitant in situ carcinoma (26/26 cases). We have also identified a new LOH loci on chromosome 8p12-21 found in more than 90% of sporadic prostate cancer (29/30 cases) and originating in a significant subset of prostate PIN (prostate intraepithelial neoplasia) lesions (26/29 informative cases). Microdissection was used to narrow the LOH region on chromosome 11 associated with the hereditary syndrome MEN-1 (multiple endocrine neoplasia type 1). In collaboration with NIDDK and NIHGR, we isolated the long MEN-1 gene. We are now attempting to study the role of MEN-1 suppressor function in a variety of tumor types.
