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bsp;  Recently, specifc genetic elements which suppess tumorigencity have been described. Several such elements have been localized to human chromosomes 11 and 13q leading to the conceptualization of cancer suppressor genes. In this paradigm, the loss of both alleles of such a suppressor gene, rather than the "activation" of a proto-oncogene, is responsible for tumorigenesis. In human retinoblastomas, the inactivation of a specific gene on chromosome 13q, called rb-l , is critical for neoplastic transformation.
     In each case described, perturbations in any one gene may be involved in different phases (early or late) of oncogenesis depending on the disease context. Also, quite frequently, many genetic abnormalities are associated with a tumor that obscures the significance of any single genetic change. Furthermore, reliance on animal model systems to explain human malignancy must be taken with some caution since evidence exists implicating different oncogenes in the genesis of similar tumors depending on the species studied (man vs. mouse).
     To this point, we have suggested some associations between oncogenes and the neoplastic state. What evidence do we have that endogenous transforming genes are involved in human cancer?
     AII of the retroviral oncogenes discovered thus far have cellular homologues (proto- oncogenes) that are thought to be involved in normal cellular function (see Chapter 5). If these normal genes are to cause cancer their structure or their expression must be perturbed. Examples of such changes include the following:
     l. Point mutations within the gene
     2. Genetic rearrangements within the coding sequence of the gene
     3. Genetic rearrangements outside the coding region
     4. Amplification and/or overexpression of the gene
     Each of these mechanisms results in the "activation" of one or another of the cellular proto-oncogenes that has been associated experimentally with human cancer. An additional mechanism for which there is preliminary experimental evidence is.
     5. Deletion of possible "anti-oncogenes"

     Point Mutations, ras Gene and Human Neoplasia

     The most notable class of oncogenes activated by point mutation is the ras family (Table 6.   l). The first activated human oncogene was isolated from a human bladder carcinoma cell line, T24, by several researchers in 1982. Shih and Weinberg initially reported that a transforming principle present in the DNA of T24 cells by could be transferred into N!H 373 cells by DNA transfection (Fig. 6.l). Specifically, genomic DNA isolated from the bladder carcinoma cell line would trans-

 

 

     TABLE 6.1 Examples of ras mutations that transform in the 3T3  focus formation assay.

ras, Allele 
Emax Source of allele Codons 
Focus formation
  12 59 61 
c-H-ras Normal human GGC GCC CAG No
  Gly Ala Glu 
c-H-ras Bladder carcinoma line GTC GCC CAG Yes
  Val Ala Gla 
c-K-ras Normal human GGT GCA CAA No
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