How Genes Cause Cancer
How do genes cause cancer?
To understand the mechanisms of how genes cause cancer, it's 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. The other copy comes from the father. Eggs and sperm are called germ cells. When a change (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. Mutations that you are not born with, but that happen 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 your children. Most human cancers are thought to be caused by acquired (somatic) mutations. Germline mutations are involved in a small portion of cases.
Tumors form when cell growth gets out of control. In the human genome, many types of genes control cell growth in a very precise way. When these genes have an error in their DNA code, they may not work properly. They are said to be altered or mutated. In most cases of cancer, many mutations must happen one after another in different genes in a specific group of cells over time to cause malignancy. The different types of mutated genes that can lead to 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 happen one after another in these genes is largely unknown. Mutations can be caused by things in the environment known to increase the risk for cancer (carcinogens). The development of mutations is also a natural part of aging.
These are altered forms of genes known as proto-oncogenes. Proto-oncogenes promote cell growth. When changed or mutated, they become oncogenes. They can then promote tumor formation or growth. Properties of oncogenes include:
Mutations in proto-oncogenes are usually acquired.
Having a mutation in just one of the 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 promoter genes contribute to development of tumors in general, or to separate aspects of tumor progression.
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 (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:
Both copies of a specific tumor suppressor gene pair need to be mutated in order to cause a change in cell growth and tumor formation to happen. 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 happen as the result of aging, environmental factors, or both.
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. It is present in all of a person's cells (germline mutation). The mutation in the second copy of the gene is acquired and usually happens only in a single cell or a handful of cells. If the second mutation happens 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 linked to hereditary cancer are tumor suppressor genes. But most mutations in tumor suppressor genes are not inherited.
DNA repair genes
During cell division, the DNA in a cell makes a copy (replica) of itself. During this complex process, mistakes may happen. Mismatch-repair genes code for proteins that correct these naturally occurring spelling errors in the DNA. When these genes are mutated, mismatches (mistakes) in the DNA remain. If these mistakes happen in tumor suppressor genes or proto-oncogenes, this will lead to uncontrolled cell growth and tumor formation. Other types of DNA repair genes repair errors in DNA that happen from mutagenic agents, such as large doses of radiation. Properties of DNA repair genes include:
Mutations in DNA repair genes can be inherited from a parent. They also be acquired over time as the result of aging and environmental factors.
DNA repair genes need mutations in both copies of the gene pair in order for the process of tumor formation to happen. For this reason, mismatch-repair genes are said to be recessive at the cellular level.
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. 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.
June 12, 2018
Berger AH. A Continuum Model for Tumour Suppression. Nature. 2011;476:163-9.
Brown, Kim, APRN,LoCicero, Richard, MD