Cancer Predisposition Genes
We inherit two copies of almost every gene - one from each parent. DNA changes that are transmitted from one generation to the next are called constitutional (inherited) mutations. This type of inherited mutation is typically present in every cell in the body, including egg and sperm cells. Consequently, we have the ability to pass down these mutations to our children.
Other DNA changes may occur sporadically in the body in a single cell or tissue. These types of DNA changes are called focal (somatic) mutations. These types of mutations are not inherited, are not present in every cell of the body, and cannot be passed down to children. The specific causes of sporadic mutations are largely unknown. However, we do know that sporadic mutations can be caused by carcinogens (environmental factors that increase cancer risk), like smoking or sun exposure; mutagenic agents, like radiation; or they can occur as a natural consequence of aging.
In cancers, sporadic mutations are always involved in the formation of a tumor, while inherited mutations are only present in a small percentage of cases.
There are multiple genes that affect and direct cell growth and death. If any one of these genes has a mutation, it may be damaged and not function properly. Over time, there is a domino effect with an accumulation of many mutations in different genes. This accumulation of genetic mistakes may lead to tumor formation and growth. There are three major categories of genes that cause predisposition to cancer. These categories include:
Oncogenes: Proto-oncogenes play important roles in our cell's signaling pathways and help maintain normal cell growth and function. When a proto-oncogene has a mutation, it becomes an oncogene. This transformation of a proto-oncogene to oncogene is called activation. With oncogenes, having a single mutation is sufficient to promote cell growth and expression. As such, mutations in oncogenes are considered "dominant" at the cellular level. Multiple activated oncogenes are typically necessary for tumor formation and growth. Oncogene activation usually occurs sporadically and few mutations are inherited.
Tumor suppressor genes: Tumor suppressor genes function to control the cell cycle and promote cell death (called apoptosis) in damaged cells. In tumor suppressor genes, it is necessary to have two mutations (one in each gene copy), to cause inactivation and subsequent deregulated cell growth and tumor formation. As such, mutations in tumor suppressor genes are considered "recessive" at the cellular level. The first mutation (or inactivated gene) can be inherited, but usually occurs sporadically. The second mutation (or inactivated gene) occurs sporadically and is not inherited.
DNA mismatch repair genes: When a cell divides, the DNA contained within the cell is replicated. During this process, mistakes can occur. In addition, when a cell is exposed to carcinogens or mutagenic agents, such as radiation, DNA mutations may be induced. It is the role of DNA mismatch repair genes to correct these mistakes. In DNA mismatch repair genes, it is necessary to have two mutations (one in each gene copy), to cause inactivation of the gene. Subsequently, this DNA repair process may not function properly and DNA mutations may accumulate. If DNA mistakes are not corrected and they are present in proto-oncogenes or tumor suppressor genes, tumor formation and growth may occur. Similar to tumor suppressor genes, mutations in DNA mismatch repair genes are considered "recessive" at the cellular level.
Hereditary Cancer Syndromes
It is estimated that about 5% to 10% of cancers have a hereditary component.
Although oncogenes, tumor supressor genes, and DNA mismatch repair genes have all been associated with hereditary cancer syndromes, the majority of hereditary cancer syndromes are caused by mutations in tumor suppressor genes. People with hereditary cancer syndromes have an increased risk to develop cancer in their lifetime that is higher than the general population cancer risk. Having an inherited cancer predisposition, however, does not mean that cancer is inevitable. Some common signs that an individual or family is at risk to have an inherited cancer predisposition include:
- There are multiple family members in more than one generation with the same or associated cancers.
- The cancers tend to occur at younger than average ages (usually <50 years).
- There is a history of two or more separate cancers (separate primaries), bilateral cancers (i.e. bilateral breast cancer), or multifocal cancers (two or more cancers in the same organ) in a single person.
- There is a rare cancer such as breast cancer in a male relative.
Some of the more common hereditary cancer syndromes include:
Each of these hereditary cancer syndromes is associated with an increased risk to develop one or more associated cancers. An individual with a cancer-predisposing mutation has a 50% chance with each pregnancy to pass down such mutation. Those in the family that inherit the mutation have a higher risk to develop the associated cancers over the general population. Those who do not inherit the mutation are typically considered at general population risk. Cancer genetic testing may help determine who in the family has an increased cancer risk. In many cases, the first step is to test the family member with cancer. If a causative mutation is found, testing can then be offered to other family members in order to help establish their cancer risk.
Genetic Conditions with an Increased Cancer Risk
In addition to the hereditary cancer syndromes, there are multiple genetic conditions in which cancer as a primary feature. These disorders cause characteristic physical and/or mental abnormalities as well as an increased risk to develop certain types of cancer. Some of these more common genetic diseases associated with an increased cancer risk include:
The pattern of inheritance and overall cancer risk differs by condition with most conditions conferring an increased lifetime cancer risk of 50% of less. A major exception is xeroderma pigmentosum (XP). People with XP have a greater than 90% lifetime risk to develop cancer. Some of these genetic conditions, including ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, and xeroderma pigmentosum, are caused by mutations in DNA mismatch repair genes. In other genetic conditions, the increased cancer risk is a result of other abnormal genetic mechanisms.
Cancer Genetic Counseling
Cancer predisposition testing is complex, and the number of genes that are being associated with a predisposition to cancer increases as research progresses. In a cancer genetic consultation, a trained genetic professional discusses the risks, benefits, and limitations of all genetic testing options, as well as any possible screening and preventative measures.
Last Reviewed January 14, 2010