Molecular genetics and chromosomal alterations in prostate cancer

The multistep nature of carcinogenesis has been repeatedly demonstrated for a variety of human cancers. Concomitant mutational activation of genes that promote cellular growth (i.e., oncogenes) and inactivation of genes that normally act to restrict or otherwise regulate growth (i.e., tumor suppressor genes) are key steps leading to tumor formation. Alterations in such genes can be restricted to the site of the cancer or can be inherited, predisposing a fraction of individuals to develop certain cancers. Evidence has been by the authors and others that chromosomes 8, 10, and 16 harbor potentially novel tumor suppressor genes that are frequently altered in prostatic carcinogenesis. Deletion mapping experiments suggest that critical genes lie on the short arm of chromosome 8 (8p22) and on the long arm of chromosome 16 (16qter‐16q22). A gene in this latter area that we believe plays a critical role in determining the aggressiveness of prostate cancer is the gene for the cell‐cell adhesion molecule, E‐cadherin. Alterations of the expression of this protein or its accessory proteins, the catenins, are found in approximately one‐half of clinically localized tumors and at a higher frequency in tumors that have metastasized (or are likely to). Experimental restoration of the E‐cadherin pathway in prostate cancer cell lines results in suppression of the malignant phenotype. The authors anticipate that understanding the mechanisms by which this and other growth regulatory pathways become altered in prostate cancer will lead to better diagnostic and prognostic markers for this common disease and will possibly identify new approaches for novel therapeutic strategies. Cancer 1995;75:2004–12.