Somatic Mutations in Tumor Suppressor Genes

27 May

As indicated  by our earlier discussions  (see above), somatic mutations  in tumor suppressor genes will effect the neoplastic transformation  only if both alleles of the suppressor gene are affected.  Because  of the relative  tissue specificity  of neoplasms  developing  in patients with germline mutations in these genes, one might expect that a similar specificity would be found in somatic mutations. In part this is true, as noted earlier (Chapter 5) by somatic mutations seen in up to 56% of clear-cell renal carcinomas (Shuin et al., 1994; Foster et al., 1994); but no muta- tions were found in non-clear-cell renal carcinomas. In addition, about 20% of sporadic central nervous  system  hemangioblastomas,  benign  neoplasms  often associated  with the von Hip- pel–Lindau  (VHL) syndrome, also exhibit somatic mutations in the VHL gene (Kanno et al.,

1994). Similarly, mutations in the APC tumor suppressor gene of hereditary familial polyposis are seen in about 60% of esophageal and gastric cancers in the human (Tahara, 1995).

Somatic mutations in tumor suppressor genes have been most extensively investigated in the Rb (retinoblastoma)  (Table 6.5) and p53 tumor suppressor genes. A surprisingly high fre- quency of mutations has been noted in the Rb gene in a number of different neoplasms in the human. As noted in the table, several of these determinations have been made through the use of the Southern blot analyses in which allelic loss (loss of heterozygosity,  or LOH) can be deter- mined (Chapter 5). Specific point mutations have not been determined in most instances, and the majority of changes are seen in carcinomas rather than benign neoplasms as exemplified by the virtual absence of Rb mutations in parathyroid adenomas (Cryns et al., 1994). The presence of deletions  within the promoter  region of the Rb gene in prostatic carcinomas,  as reported by Bookstein et al. (1990), was later not confirmed by Sarkar et al. (1992). Osteosarcomas are the most common second malignancy found in individuals with hereditary retinoblastoma. A loss of

heterozygosity for chromosome 13 probes has been observed in individuals with osteosarcoma, whether or not these patients had a previous history of retinoblastoma (cf. Benedict et al., 1990). In a series of some 30 cases of primary osteosarcoma, 13 exhibited structural abnormalities in the Rb gene (Toguchida et al., 1988). Other sporadic soft-tissue sarcomas exhibited somatic mu- tations in the Rb gene (Weichselbaum et al., 1988) with the exception of childhood rhabdomyo- sarcomas  (De Chiara  et al., 1993).  However,  in osteosarcomas  arising  in mixed  gonadal neoplasms, somatic mutations in Rb are unusual (Reuvekamp et al., 1992). Thus, somatic muta- tions in the Rb tumor suppressor gene have been reported in a number of nonocular neoplasms. This phenomenon is even more extensively seen in the p53 tumor suppressor gene.

Random Posts

Comments are closed.