Inactivation of Tumor Suppressor Genes

Sequential mutations within colonic epithelium result in cellular replication or enhanced invasiveness. Genetic changes include mutational activation of oncogenes and inactivation of tumor suppressor genes. 

B. Loss or inactivation of tumor suppressor genes may lead to cancer. 

Tumor suppressor genes are genes that, by their inactivation due to mutations or deletion, promote tumor formation. The proteins for which they code are known as tumor suppressor proteins. Many of the known tumor suppressor proteins have a suppressing and negatively regulating effect on processes that are either directly associated with regulation of cell division or influence this in an indirect way. Other, equally important functions of tumor suppressor proteins are in the areas of DNA repair and cell adhesion. Inactivation of tumor suppressor genes can have various consequences ... 

Inactivation of tumor suppressor genes (growth and survival promoting)... 

The body has defensive mechanisms against the development of cancer in the form of tumor suppressor genes. Whereas the activation of oncogenes can cause cancer to develop, the inactivation of tumor suppressor genes disables the normal mechanisms that prevent cancerous cells from developing. Both the activation of oncogenes and the inactivation of tumor suppressor genes contribute to the development of many kinds of cancer. 

Alpha radiation from plutonium produces cytotoxic and genotoxic effects in cultured cells. These can include cell death, chromosomal aberrations (dicentrics, translocations, and complex exchanges), and pretransformation molecular alterations such as upregulation of oncogene products coupled with inactivation of tumor suppressor genes. 

Mechanisms that may be involved in the induction of cancer by radiation have been proposed. These mechanisms include (1) the induction of mutations, (2) the activation of oncogenes, (3) the inactivation of tumor suppressor genes, and (4) the induction of cancer-causing viruses. Although the relative importance of the various mechanisms in the induction of cancer is not clear, more than one mechanism could be involved for a given type of cancer. 

As we discuss in detail in Chapter 23, inactivation of tumor-suppressor genes contributes to the development of cancer. The proteins encoded by several tumor-suppressor genes, including ATM and Chk2, normally function in the DNA-damage checkpoint. Patients with mutations in both copies of ATM or Chk2 develop cancers far more frequently than normal. Both of these genes encode protein kinases. 

Cancer results from the multistep accumulation of somatic, and occasionally inherited, mutations that lead to clonal neoplastic cell transformation [1]. The associated genetic lesions include the activation of dominant oncogenes and the inactivation of tumor suppressor genes through mutation and loss of heterozygosity. Some 191 cancer genes have been reported, 90% of them exhibiting somatic mutations [2]. 

---