SPECULATIONS ON THE ROLES OF RB1 IN TISSUE-SPECIFIC DIFFERENTIATION, TUMOR INITIATION, AND TUMOR PROGRESSION

Studies of retinoblastoma clearly identify mutation of the RB1 gene on chromosome 13 as the primary cause of this cancer. However, all retin oblastoma tumors have an abnormal karyotype (1, 2) indicating the pres ence of additional mutations and suggesting that mutation of both RB1 alleles is insufficient for development of retinoblastoma. In addition , analysis of RB1 expression and of RB1 mutations in different tumors leads to the following dilemma: while the RB1 gene product, p110RB1, i s expressed in most dividing cells, germline mutations inactivating th e function of p110RB1 predispose primarily to retinoblastoma and to a lesser extent to osteosarcoma, but do not predispose to cancer in gene ral. However, many tumors contain somatic mutations that disrupt RB1 f unction. Thus, we are faced with the unusual situation in which germli ne mutations in the RB1 gene predispose to a very limited set of cance rs, but somatic mutations in RB1 appear to contribute to malignancy in many tissues. We propose that the role of the RB1 gene is to maintain the cells in a stable, quiescent state required for terminal differen tiation and that the effect of RB1 mutations in different tissues depe nds on the pattern of differentiation in that tissue. In tissues where differentiation follows a linear process from undifferentiated precur sors to fully differentiated cells, loss of RB1 function during early stages of differentiation may lead to uncontrolled growth and the deve lopment of cancer. On the other hand, in cell renewal systems where ce ll number is usually maintained by a process of programmed cell death (PCD) or apoptosis, loss of RB1 function may lead to cell death.