Oncogenes have been implicated in the development of a number of human neoplasms. Oncogene activation is believed to be required for oncogenesis. Which of the following potential mechanisms are relevant to these processes?

a. Chromosome translocation

b. DNA point mutation

c. Amplification 

Cellular proto-oncogenes are key regulatory components in cell growth, and many proto-oncogenes are expressed during periods of proliferation, development, and differentiation. Abnormal proto-oncogene function or activation may, therefore, result in the deregulated proliferation and dedifferentiation characteristic of the neoplastic state. Various activation mechanisms can change a normal gene into an oncogene. Point mutations (single nucleotide changes in DNA) are one such mechanism. For example, members of the ras gene family are some of the most frequently activated oncogenes in solid human tumors. The ras gene products are plasma membrane proteins capable of binding guanosine triphosphate (GTP). These proteins, called G proteins, are involved in intracellular signal transduction. In tumors with ras activation, the difference in the oncogene compared to the normal gene is a single nucleotide change. Point mutations resulting in single amino acid substitutions in the ras protein change a normal protein into one with transforming activity.

Another important mechanism of oncogene activation is chromosomal translocation, the shifting of a segment of one chromosome to another chromosome. One of the most well-known examples is the formation of the Philadelphia chromosome in chronic myelogenous leukemia. The proto-oncogene c-abl is translocated from chromosome 9 to the bcr locus on chromosome 22. Transcription of the new bcr/abl locus results in the formation of a fusion protein. This new protein has enhanced tyrosine kinase activity and transforming capabilities. In other tumors, an oncogene may be found in an increased number of gene copies per cell, termed amplification. DNA amplification results in an increased level of gene expression. Amplification of N-myc has been found to correlate with prognosis in patients with neuroblastoma.