On the basis of studies in animals with carcinogenic retroviruses, one might expect that muta- tions in proto-oncogenes would be a major cause of germline neoplasia in the human. We have already seen that this is generally not true, with the ret proto-oncogene being the only known example of a causative association with specific human neoplasms (Tables 5.4 and 5.6). Evi- dence that mutations in proto-oncogenes play any role in a genetic predisposition to neoplasia has been somewhat controversial. In 1987 Krontiris reported that rare alleles of the Ha-ras proto-oncogene were almost exclusively seen in the genomes of cancer patients (Krontiris et al., 1987). Since that time, other studies (Klingel et al., 1991; Ryberg et al., 1992) have shown a somewhat similar effect in German patients with colorectal cancer and in Norwegians with lung cancer, respectively. Krontiris and associates (1993) have also extended their investigations and proposed that 1 in 11 cancers of the breast, colon, and bladder possess such mutant alleles. On the other hand, Hall et al. (1990a) were unable to find such an association, and Peto et al. (1988) argued that there was no clear evidence of Ha-ras polymorphic alleles and cancer development. A number of other negative studies in leukemias and lymphomas have been reported (Trench et al., 1989; Knauf and Ho, 1991). A germline mutation in the mos proto-oncogene was uniquely detected in a small series of patients with breast cancer (Lidereau et al., 1988), while a specific allele of the myc proto-oncogene was significantly increased in males with bone and soft-tissue sarcomas (Kato et al., 1990). Thus, the role of germline mutations in proto-oncogenes in cancer susceptibility with the exception noted above has not yet been clarified. On the other hand, given the considerable experimental basis and the suggestion of positive effects noted above, it is likely that mutations in such genes may play a role in the multifactorial origin of neoplasia. In contrast, as noted further on (Chapter 6), somatic mutations in proto-oncogenes appear to play significant roles in cancer growth and development.