The genetic changes found in cancers vary from point mutations involving single nucleotides to abnormalities large enough to produce gross changes in chromosome structure. In certain neoplasms, genetic abnormalities are nonrandom and highly characteristic. Specific chromosomal abnormalities have been identified in most leukemias and lymphomas and in an increasing number of nonhematopoietic tumors, while other tumors are characterized by particular point mutations. It is believed that all recurrent genetic changes alter the activity of one or more cancer genes in a fashion that gives the affected cells a selective advantage, presumably by contributing to one or more of the hallmarks of cancer.
In the following sections, we briefly review the types of mutations that are commonly found in cancers. Before doing so, however, we must first touch on the important concept of driver mutations and passenger mutations.
Driver mutations are mutations that alter the function of cancer genes and thereby directly contribute to the development or progression of a given cancer. They are usually acquired, but as mentioned earlier, occasionally inherited. By contrast, passenger mutations are acquired mutations that are neutral in terms of fitness and do not affect cellular behavior; they just come along for the proverbial ride. Because they occur at random, passenger mutations are sprinkled throughout the genome, whereas driver mutations tend to be tightly clustered within cancer genes. It is now appreciated that particularly in cancers caused by carcinogen exposure, such as melanoma and smoking-related lung cancer, passenger mutations greatly outnumber driver mutations.
Despite their apparently innocuous nature, passenger mutations have nevertheless proven to be important in several ways:
In carcinogen-associated cancers, mutational analysis has provided definitive evidence that most genomic damage is directly caused by the carcinogen in question. For example, before sequencing of melanoma genomes, the causative role of sun exposure in this cancer was debated. This is no longer so, as most melanomas have thousands of mutations of a type that is specifically linked to damage caused by ultraviolet light.
A second, more nefarious effect of passenger mutations is that they create genetic variants that, while initially neutral, may provide tumor cells with a selective advantage in the setting of therapy. The evidence for this comes from DNA sequence analyses of tumors at the time of recurrence after drug therapy; in many instances, mutations that lead directly to drug resistance are found in most tumor cells. Generally, the same resistance mutations can also be found before therapy, but only in a very small fraction of cells. In such instances, it appears that the selective pressure of therapy “converts” a neutral passenger mutation into a driver mutation, to the benefit of the tumor and the detriment of the patient.
Point mutations can either activate or inactivate the protein products of the affected genes depending on their precise position and consequence. Point mutations that convert proto-oncogenes into oncogenes generally produce a gain-of-function by altering amino acid residues in a domain that normally holds the protein’s activity in check. A cardinal example is point mutations that convert the RAS gene into a cancer gene, one of the most comment events in human cancers. By contrast, point mutations (as well as larger aberrations, such as insertions and deletions) in tumor suppressor genes reduce or disable the function of the encoded protein. The tumor suppressor gene that is most commonly affected by point mutations in cancer is TP53, a prototypical “guardian” type tumor suppressor gene (discussed later).
Gene rearrangements may be produced by chromosomal translocations or inversions. Specific chromosomal trans-locations and inversions are highly associated with certain malignancies, particularly neoplasms derived from hematopoietic cells and other kinds of mesenchymal cells.
http://ebooksmedicine.net
These rearrangements can activate proto-oncogenes in two ways: