What is hereditary breast/ovarian cancer (HBOC) syndrome?
Most cancers are sporadic but approximately 15% of cancers may be hereditary. This seems to be true for both breast and ovarian cancers.
Hereditary breast/ovarian cancer (HBOC) syndrome is characterized by the following features in a family:
- an early age of onset of breast cancer (often before age 50)
- family history of both breast and ovarian cancer
- increased chance of bilateral cancers (cancer that develop in both breasts, or both ovaries, independently) or an individual with both breast and ovarian cancer
- an autosomal dominant pattern of inheritance (vertical transmission through either the mother or father’s side of the family)
- an increased incidence of tumors of other specific organs, such as the prostate
- family history of malebreast cancer
- frequently Ashkenazi Jewish ancestry
In 1990, DNA linkage studies on large families with the above characteristics identified the first gene associated with breast cancer. Scientists named this gene “breast cancer 1” or BRCA1 (pronounced brak-uh one). BRCA1 is located on chromosome 17. Mutations in the gene are transmitted in an autosomal dominant pattern in a family. BRCA1 is a human caretaker genethat produces a proteincalled breast cancer type 1 susceptibility protein, that is expressed in the cells of breast and other tissue, where it has an important role in the error-free repair of DNAdouble strand breaks, or destroy cells if DNA cannot be repaired. If BRCA1 itself is damaged, damaged DNA is not repaired properly and this increases the risk for cancers. The protein encoded by this gene is involved in the repair of chromosomaldamage with.\
However, it was clear that not all breast cancer families were linked to BRCA1. Studies continued and in 1994, scientists discovered another gene (similar to BRCA1), and named it BRCA2. BRCA2 is located on chromosome 13. Mutations in this gene are also transmitted in an autosomal dominant pattern in a family.
Both BRCA1 and BRCA2 are tumor suppressor genes that usually have the job of controlling cell growth and cell death. Everyone has two BRCA1 (one on each chromosome #17) and two BRCA2 genes (one on each chromosome #13). When a person has one altered or mutated copy of either the BRCA1 or BRCA2 gene, their risk for various types of cancer increases:
Although the structures of the BRCA1and BRCA2 genes are very different, at least some functions are interrelated. The proteins made by both genes are essential for repairing damaged DNA. A mutated BRCAgene makes a protein that does not function properly because it is abnormally short. Researchers believe that the defective BRCA protein is unable to help fix mutations that occur in other genes. These defects accumulate and may allow cells to grow and divide uncontrollably to form a tumor.
Both copies of a tumor suppressor gene must be altered or mutated before a person will develop cancer. In HBOC, the first mutation is inherited from either the mother or father and is therefore present in all cells of the body. This is called a germline mutation. Whether a person who has a germline mutation will develop cancer and where the cancer(s) will develop, depends upon where (in which cell type) the second mutation occurs. For example, if the second mutation is in the ovary, then ovarian cancer may develop. If it is in the breast, breast cancer may develop. The process of tumor development actually requires mutations in multiple growth control genes. Loss of both copies of BRCA1 or BRCA2 is just the first step in the process. What causes these additional mutations to be acquired is unknown. Possible causes include chemical, physical, or biological environmental exposures, or chance errors in cell replication.
Some individuals who have inherited a germline BRCA1 or BRCA2 mutation neverdevelop cancer because they never get the second mutation necessary to knock out the function of the gene and start the process of tumor formation. This can make the cancer appear to skip generations in a family, when, in reality, the mutation is present in all generations. Persons with a mutation, regardless of whether they develop cancer, have a 50/50 chance of passing the mutation on to the next generation.
It is also important to remember that the BRCA1 and BRCA2 genes are not located on the sex chromosomes. Therefore, mutations can be inherited from the mother or the father’s side of the family. When there is a family history of male breast cancer, there is a high likelihood of HBOC; however, the incidence of male carriers of the BRCA1 and BRCA2 genes developing breast cancer is approximately 6%.
People who have two mutated copies of the BRCA2 gene have one type of Fanconi anemia. This condition is caused by extremely reduced levels of the BRCA2 protein in cells, which allows the accumulation of damaged DNA. Patients with Fanconi anemia are prone to several types of leukemia(a type of blood cell cancer); solid tumors, particularly of the head, neck, skin, and reproductive organs; and bone marrow suppression (reduced blood cell production that leads to anemia).
What is a founder's effect?
One final point that needs to be understood about BRCA1 and BRCA2 is a concept known as the “founder effect." The majority of people who have a BRCA1 or BRCA2 mutation have a unique mutation, one that is specific to them and their family. To date, hundreds of unique mutations have been identified in both BRCA1 and BRCA2. However, there are a few exceptions. For instance, specific recurring mutations have been found in individuals of Ashkenazi Jewish descent, and persons from the Netherlands, Iceland, and Sweden. The same mutations recur in these groups because of a founder’s effect. "Founders" are a small group of people who, due to geographic or religious isolation, intermarried. When a small group of people interbreeds over generations, specific rare mutations can recur and become more common in that population. This is called a founder’s effect.
The present day Ashkenazi Jewish population arose from a small group of founders, of whom one or more must have carried specific mutations in the BRCA1 and BRCA2 genes. In particular, there are three mutations (two in BRCA1 and one in BRCA2) that account for the majority of the BRCA mutations seen in persons of Ashkenazi Jewish ancestry. This information has practical meaning when it comes to genetic testing because some laboratories now offer “ethnic-specific” mutation panels. Rather than searching through the entire gene every time a person is tested, in some cases, laboratories can instead first look for specific mutations based on a person’s ethnic background. The founder effect is also important in Ashkenazi Jewish individuals because it has led to an increased occurrence of BRCA mutations in this population. In the general population, it is estimated that one in 800 individuals has a mutation in BRCA1 or BRCA2. In contrast, one in 40 Ashkenazi individuals has one of the recurring mutations. This increased occurrence has implications in terms of assessing the significance of a family history of breast and ovarian cancer in Ashkenazi versus non-Ashkenazi persons.
Women having inherited a defective BRCA1 or BRCA2 gene have risks for breast and ovarian cancer that are so high that many mutation carriers choose to have prophylactic surgery such as bilateral oophorectomy and mastectomies.