In order to understand the genetic mechanisms of how genes cause cancer, it is important to review some basic genetic concepts. Genes come in pairs, and work together to make a protein product. One copy of the gene pair comes from the mother, while the other copy is inherited from the father. Eggs and sperm are called germ cells. When a change or mutation in a gene is present in the germ cells, it is referred to as a germline mutation. When a germline mutation is inherited, it is present in all body cells from birth. On the other hand, mutations that we are not born with, but that occur by chance over time, are said to be acquired. Acquired mutations are not present in all cells of the body, are not inherited, and are not passed down to our children. Most human cancers are thought to be caused by acquired mutations. Germline mutations are involved in a small percentage of cases.
The formation of tumors is caused by cell growth that gets out of control. In the human genome, there are many different types of genes that control cell growth in a very systematic, precise way. When these genes have an error in their DNA code, they may not work properly, and are said to be altered or mutated. In most cases of cancer, many mutations must occur in different genes in a specific group of cells over time to cause malignancy. The different types of genes that, when mutated, can lead to the development of cancer are described below. Remember, it usually takes mutations in several of these genes for a person to develop cancer. What specifically causes mutations to occur in these genes is largely unknown. Mutations can be caused by carcinogens (environmental factors known to increase the risk of cancer), but the development of mutations is also a natural part of the aging process.
Oncogenes. These are altered forms of genes known as proto-oncogenes. Proto-oncogenes are responsible for promoting cell growth. When changed or mutated, they become oncogenes and can then promote tumor formation or growth. Properties of oncogenes include the following:
Mutations in proto-oncogenes are usually acquired. One exception is that mutations in the RET proto-oncogene can be inherited and cause a condition called multiple endocrine neoplasia (MEN) type II.
Having a mutation in just one of the two copy pair of a particular proto-oncogene is usually enough to cause a change in cell growth and the formation of a tumor. For this reason, oncogenes are said to be dominant at the cellular level.
Tumor suppressor genes. Tumor suppressor genes are normally present in our cells. When working properly, they keep the processes of cell growth and cell death (called apoptosis) in check. Through these processes, they can also suppress tumor development. When a tumor suppressor gene is mutated, this can lead to tumor formation or growth. Properties of tumor suppressor genes include the following:
Both copies of a specific tumor suppressor gene need to be mutated (both members of the gene pair) in order to cause a change in cell growth and tumor formation to occur. For this reason, tumor suppressor genes are said to be recessive at the cellular level.
Mutations in tumor suppressor genes are often acquired. Mutations in both copies of a tumor suppressor gene pair may occur as the result of aging and/or environmental exposures.
A mutation in a tumor suppressor gene can also be inherited. In these cases, a mutation in one copy of the tumor suppressor gene pair is inherited from a parent, and is present in all of a person's cells (germline mutation). The mutation in the second copy of the gene (which is necessary for tumor formation and cell growth change) is acquired and usually occurs only in a single cell or a handful of cells. If the second hit or mutation occurs in a type of cell that needs this particular tumor suppressor gene to control cell growth, the process of tumor formation will begin. This mechanism is also known as the two-hit hypothesis.
Most of the genes associated with hereditary cancer are tumor suppressor genes. Nonetheless, most mutations in tumor suppressor genes are not inherited.
DNA repair genes. During cell division, the DNA in a cell makes a copy, or replica, of itself. During this complex process, mistakes may occur. Mismatch-repair genes code for proteins that correct these naturally occurring spelling errors in the DNA. When these genes are altered or mutated, however, mismatches (mistakes) in the DNA remain. If these mistakes occur in tumor suppressor genes or proto-oncogenes, eventually this will lead to uncontrolled cell growth and tumor formation. There are other types of DNA repair genes that repair errors in DNA that occur from mutagenic agents, such as large doses of radiation. Properties of DNA repair genes include the following:
Mutations in DNA repair genes can be inherited from a parent or acquired over time as the result of aging and environmental exposures.
DNA repair genes require two mutations (both copies of the gene pair) in order for the process of tumor formation to occur. For this reason, mismatch-repair genes are said to be recessive at the cellular level.
Remember that it usually takes mutations in several of these genes for cancer to develop. In most cases of cancer, all the mutations are acquired. In inherited cancer, one mutation is passed down from the parent, but the remainder are acquired. Because it takes more than a single mutation to cause cancer, not all people who inherit a mutation in a tumor suppressor gene, proto-oncogene, or DNA repair gene will develop cancer within their lifetime.