A new functional classification of tumor-suppressing genes and its therapeutic implications

Cell fusion studies have demonstrated that malignancy can be suppressed by a single dose of malignancy suppressor genes (MSGs), indicating that malign ancy is a recessive phenotype. Correspondingly, it is widely believed that mutational inactivation of both alleles of tumor suppressor genes (TSGs), i n familial and sporadic tumors, is the formal proof of the recessive nature of malignancy. Evidence presented here, however, shows that unlike MSGs, i dentified solely through cell fusion studies with no gene of this class yet cloned, many well-known TSGs have gene dosage effects and inhibit cellular growth in vitro. Moreover, homozygous inactivation of a growth-inhibitory TSG (GITSG) is not directly correlated with malignancy. An alternative inte rpretation is provided for the loss of wild-type alleles of these genes in the tumors. It is concluded that the MSGs and the GITSGs do not belong to t he same class of genes, The functional classification of tumor-suppressing genes has important implications for developing effective cancer therapies. (C) 2000 John Wiley & Sons, Inc.