It could be argued that the proliferation of literature on the molecular basis of cancer has outpaced the growth of even the most malignant of tumors. Researchers and students alike can easily get lost in the growing forest of information. But it has become eminently clear that cancer is a disease caused by mutations that alter the function of of a finite subset of the 20,000 or so human genes. For simplicity, we will refer to these genes as cancer genes. Cancer genes can be defined as genes that are recurrently affected by genetic aberrations in cancers, presumably because they contribute directly to the malignant behavior of cancer cells. Causative mutations that give rise to cancer genes may be acquired by the action of environmental agents, such as chemicals, radiation, or viruses, may occur spontaneously, or may be inherited in the germ line. If such mutations drive carcinogenesis, a key prediction is that each cell in an individual tumor should share mutations that were present in the founding cell at the time of transformation. This expectation has been realized in all tumors that have been systematically analyzed by genomic sequencing, providing strong support for the hypothesis that cancer is at its root a genetic disease.
Cancer genes number in the hundreds and new ones are still being discovered. Not only are these genes numerous, but many have unpronounceable acronyms for names that are difficult to remember, even for the aficionado. One way to try to simplify this complexity is to consider that cancer genes fall into one of four major functional classes:
Oncogenes are genes that induce a transformed phenotype when expressed in cells by promoting increased cell growth. A major discovery in cancer was the realization that oncogenes are mutated or overexpressed versions of normal cellular genes, which are called proto-oncogenes. Most oncogenes encode transcription factors, factors that participate in pro-growth signaling pathways, or factors that enhance cell survival. They are considered dominant genes because a mutation involving a single allele is sufficient to produce a pro-oncogenic effect.
Tumor suppressor genes are genes that normally prevent uncontrolled growth and, when mutated or lost from a cell, allow the transformed phenotype to develop. Often both normal alleles of tumor suppressor genes must be damaged for transformation to occur. Tumor suppressor genes can be placed into two general groups, “governors” that act as important brakes on cellular proliferation, and “guardians” that are responsible for sensing genomic damage. Some guardian genes initiate and choreograph a complex “damage control response” that leads to the cessation of proliferation or, if the damage is too great to be repaired, or induce apoptosis.
Genes that regulate apoptosis primarily act by enhancing cell survival, rather than stimulating proliferation per se. Understandably, genes of this class that protect against apoptosis are often overexpressed in cancer cells, whereas those that promote apoptosis tend to be under-expressed or functionally inactivated by mutations.
To this list may now be added genes that regulate interactions between tumor cells and host cells, as these genes are also recurrently mutated or functionally altered in certain cancers. Particularly important are genes that enhance or inhibit recognition of tumors cells by the host immune system.
In most instances, the mutations that give rise to cancer genes are acquired during life and are confined to the cancer cells. However, causative mutations sometimes are inherited in the germ line and are therefore present in http://ebooksmedicine.net
Neurofibromatosis1and2NF1, NF2
BreastandovariantumorsBRCA1, BRCA2
Multipleendocrineneoplasia1and2MEN1, RET
HereditarynonpolyposiscoloncancerMSH2, MLH1, MSH6 every cell in the body, placing the affected individual at high risk for developing cancer. Understandably, in families in which these germ line mutations are passed from generation to generation, cancer behaves like an inherited trait (
Table 6.4 ). We will touch on important familial cancer syndromes and associated genes and cancers later in this chapter.
Presented next is a discussion of the varied genetic lesions that underlie altered cancer gene expression and function.