Transformation and Oncogenesis by Damaging the Chromosome

Transformation and Oncogenesis by Damaging the Chromosome

Epidemiologists have long recognized that certain chemicals induce cancer, and Ames has shown that many bacterial mutagens are human carcinogens. The mutagenicity of chemicals, as detected by the rever-sion of a set of bacterial histidine mutants, correlates well with their carcinogenicity. Therefore chromosome damage in the form of muta-tions or small insertions and deletions is one cause of cancer. The next section explains how the exact base change responsible for induction of one particular cancer was determined.

Figure 23.3 Human and mouse translocations associated with cancers of theimmune system.

In addition to small lesions, chromosomal rearrangements can alter either the expression or the structure of RNAs or proteins. Such chro-mosomal rearrangements are frequently observed in a class of cancers called Burkitt’s lymphomas in humans and plasmacytomas in mice. These are cancers of immunoglobulin-secreting cells, and therefore it is likely that the chromosome rearrangements in Burkitt’s lymphomas actually involve the immunoglobulin genes. Indeed, the chromosomes involved in the rearrangements usually are those that contain the heavy and light immunoglobulin genes (Fig. 23.3). The actual site of the chromosomal translocation in a Burkitt’s lymphoma can be identified by cloning the heavy chain constant region from lymphoma and non-lymphoma cells. Many lymphomas contain a translocation that fuses part of chromosome 8 to a heavy chain switch region on chromosome 14 (Fig. 23.4). The junction of the translocation sometimes contains a sequence resembling the DNA it replaced, implying that a recombina-tion event, or an immunoglobulin switch-related event, was responsible for the translocation. The DNA that has been translocated to the immunoglobulin region codes for one of the cell’s growth regulators known as c-myc.

Figure 23.4 Schematic of the heavy chain region of human chromosome 14and the approximate location of the material from chromosome 8 that is translocated to chromosome 14. Transcripts originating in the region are also shown.

 As a result of the translocation, its expression is deregulated and its gene is often slightly rearranged. Similar gene translocations of c-myc are also involved with mouse plasmacytomas.