Chicago Center for Jewish Genetics Disorders - Health Professionals

BRCA1 and BRCA2 Specifics

Five to 10% of all breast and ovarian cancer cases are thought to be due to an inherited cause. BRCA1 and BRCA2 are thought to be responsible for 1 to 5% of all breast and ovarian cancer cases, or 60 to 65% of the inherited cases. From studies of cancer-prone families, BRCA1 and BRCA2 cancer-predisposing mutations have been estimated to occur in approximately one to two persons per thousand. From high-risk family studies, an individual with a BRCA1 or BRCA2 mutation has an estimated 50 to 85% risk over her lifetime for breast cancer (often at an early age) and a 20 to 54% lifetime risk for ovarian cancer. Mutation carriers who develop breast cancer also have a 40 to 65% lifetime risk of developing a second breast tumor.

BRCA1 and BRCA2 are tumor suppressor genes and are considered breast and ovarian cancer predisposition genes. The BRCA1 gene is located at 17q21 and the BRCA2 gene is located at 13q12.3. In addition, they both serve as a “caretaker,” helping to maintain integrity of the genome by being involved in DNA synthesis and repair. If this function is lost, it might allow for the accumulation of other genetic defects that are themselves directly responsible for cancer formation.

Over 600 different mutations have been identified in BRCA1 and several hundred have been found in BRCA2, with the vast majority of families having their own “private mutation.” There may be differences in cancer risk associated with different mutations, but not enough data is yet available to determine this. About a third of mutations identified in either the BRCA1 or BRCA2 gene so far are of uncertain clinical significance and further research will need to be done to clarify their possible pathogenicity.

The penetrance for mutations in either gene is uncertain and probably variable. Therefore, some individuals with cancer-predisposing mutations survive to an elderly age without developing cancer, while other individuals with the same mutation develop cancer. Among those who develop cancer, the age of onset, as well as type of cancer, varies. There is no difference in survival between individuals with cancer who have a BRCA1 or BRCA2 mutation and those without a mutation. Tumors with BRCA1 and BRCA2 mutations have been found to have pathological differences from sporadic tumors and may have differences (BRCA 1) in their hormonal responsiveness. It should also be noted that sporadic tumors rarely have BRCA1 and BRCA2 mutations. For more information, see Pathogenicity of BRCA1 and BRCA2 Mutations.

BRCA1 and BRCA2 are autosomal recessive in function and both copies of the BRCA1 or BRCA2 gene need to be mutated before control of cell growth is lost. However, mutations appear autosomal dominant in a family due to the high likelihood of developing a second mutation in the other copy of the same cell. This is because of the high penetrance of the mutations and this is explained by a theory called Knudson’s Hypothesis. This theory explains why an individual who has a germline BRCA1 or BRCA2 mutation has a much higher lifetime risk to develop cancer than an individual born with two functional copies of the gene. A single germline mutation does not cause cancer; it is not until the other copy of the BRCA1 or BRCA2 gene is mutated that progression to cancer can occur. In an individual born with one mutation in all of their cells, it is much more likely that a second mutation will occur in the other copy in any one cell than in an individual who first has to have a mutation in one copy of the gene in one cell and then a second mutation in the other copy in the same cell. Additionally, because BRCA1 and BRCA2 mutations are highly penetrant, an individual with two mutations is highly likely to develop disease. An individual with a germline (inherited) BRCA1 or BRCA2 mutation has a greater than 50% chance of developing breast cancer in their lifetime. Thus the inheritance pattern in a family appears to be autosomal dominant despite being autosomal recessive in function.

Pathogenicity of BRCA1 and BRCA2 Mutations

Breast cancer in individuals with BRCA1 or BRCA2 cancer-predisposing mutations is thought to have a specific pathogenic basis because of the distinct pathological features seen in BRCA1 and BRCA2 tumors. BRCA1 and BRCA2 mutations are also rarely seen in sporadically occurring breast cancer, which means that the vast majority of BRCA1 and BRCA2 mutations are inherited. Both of these factors might possibly lead to differences in prognosis, but there are no accurate estimates of breast cancer prognosis in individuals with a BRCA1 or BRCA2 cancer-predisposing mutation at this time. Of the many studies completed to date, when taking into account their specific limitations, no consistent significant differences in survival has been found between individuals diagnosed with cancer who either have a BRCA1 or BRCA2 mutation and those who do not.

Surveillance and Management for BRCA1 and BRCA2 Mutation Carriers

For individuals known to have a BRCA1 or BRCA2 cancer-predisposing mutation, the Cancer Genetics Consortium has recommended the following surveillance guidelines:

Monthly breast self-exams, beginning in early adulthood
Annual to semi-annual clinical breast exams, beginning at age 25 to 35 years
Annual mammography beginning at age 25 to 35 years
Annual pelvic exam, beginning at age 25 to 35 years
Transvaginal ultrasound, beginning at age 25 to 35 years
CA125 blood serum level, beginning at age 25 to 35 years. Please see Surveillance for Ovarian Cancer for more information.

Other methods of breast cancer surveillance have been proposed, such as magnetic resonance imaging (MRI) and ductal lavage. Both of these methods may have an advantage over mammography because they do not use radiation. This may be important for BRCA1 and BRCA2 mutation carriers because some studies have indicated that these carriers may be more sensitive to radiation than members of the general population. However, this possibility needs to be further explored. Studies are still being done to detect the sensitivity and specificity of breast MRIs and ductal lavage surveillance for breast cancer.

Women with BRCA1 or BRCA2 mutations may also wish to consider prophylactic removal of their breasts (mastectomy) and/or ovaries (oophorectomy). These surgeries have been proposed as a way to reduce the cancer risk in women known to have predisposing mutations but who have never been diagnosed with breast or ovarian cancer. It may also be beneficial for women who have already been diagnosed with breast and ovarian cancer because BRCA1 and BRCA2 mutation carriers have been found to be at increased risk to develop secondary primary cancers (a second tumor in the same tissue). One study has shown that the lifetime risk to develop a secondary primary breast cancer is 64% in BRCA1 mutation carriers and 56% in BRCA2 mutation carriers. At this time, there is insufficient evidence to formally recommend that these surgeries be done, however some studies have shown a reduction in breast cancer in women who had a mastectomy or an oophorectomy.

Although men with BRCA2 and to a lesser extent BRCA1 mutations may also be at increased risk for breast cancer, no formal surveillance recommendations are currently in place. However, a man should have an evaluation of any breast mass or change.

Carriers of BRCA2 mutations are also at increased risk to develop pancreatic cancer, with approximately 1 in 10 carriers developing pancreatic cancer in their lifetime. Pancreatic cancer, unless caught early, is incurable and is the most lethal cancer of which BRCA2 carriers are at risk. Both men and women with known BRCA2 mutations should discuss detection of pancreatic cancer with their physician.

Finally, BRCA1 and BRCA2 are associated with an increased risk for prostate cancer in males. Therefore, men with known mutations should discuss earlier than average screening with their doctor.

The most recent studies indicate that BRCA1 and BRCA2 mutation carriers are not at an increased risk for colon cancer, contrary to previous reports. Therefore, earlier or different screenings are not recommended for individuals with a BRCA1 or BRCA2 mutation compared to the general population.

Possibilities For BRCA3

Since familial forms of breast cancer only account for 5-10% of cases and BRCA1 and BRCA2 together account for approximately 60% of these cases, it has been hypothesized that there are more high penetrance breast cancer genes that have not yet been discovered. Intensive research has been done to try to find a possible BRCA3 or BRCA4. Recent data from two proposed chromosomal locations, D13S1308 located at 13q21 and D8S505 located at 8p12-p22, has suggested the possibility that these loci might correlate with a supposed BRCA3 or BRCA4 gene but not all studies support this. Further research will need to be done before a discovery of BRCA3 or BRCA4 is made and verified.