Gene is a particular sequence of nucleotide which codes for a protein product. BRCA gene is abbreviation for BReast CAncer gene. BRCA 1 and BRCA 2 genes have association with developments of breast cancer in humans.
Both of BRCA gene prevent cancer development in normal functional state. These are not only tumor suppressor gene but also repair the DNA breaks to prevent mutation which later on results in cancerous cells development.
Mutation as we know is sudden change in sequence and structure of DNA which usually results in loss of function. If we just consider women, one in every eight females has chances of being diagnosed with BRCA mutation. Before the age of 70, bout 55-65 % of these females with BRCA mutation develops breast cancer. Moreover, once a woman is diagnosed with breast cancer, the chances are high to develop it against even after successful treatment.
Functions of BRCA 1 and BRCA 2 genes
BRCA genes are tumor suppressor genes in humans. Both of these genes code for proteins which is involved in DNA repair. This DNA repair prevents the development of abnormal cells with uncontrolled division.
Mutation in these genes results in lack of protein product that eventually results in cancerous cells development and tumor formation. Similar to all other genetic mutations, BRCA gene mutation also passes on to offspring of the affected parents. Having a history of BRCA gene mutation or we can say having a family history of breast cancer adds up chances of a person to have breast cancer in early age.
BRCA gene mutation is not only associated with breast cancer, but also other forms of cancer including ovarian cancer, prostate cancer and fallopian tube cancer.
What statistics say?
The statistic shows that having a BRCA mutation significantly increase the risks of cancer development. For instance, about 12 % of women develop breast cancer once in their life. Studies show that 72% women inherit BRCA1 while 69% women inherit BRCA 2 mutation and most likely to develop breast cancer before age 70.
Moreover, about 13% of women population develops ovarian cancer once in lifetime. About 42% have BRCA 1 gene mutation and 17% inherit BRCA 2 mutation.
In addition to cancer development, BRCA 2 gene mutation and its variant alleles may cause Fanconi anemia (FANCD1). This is comparatively rare case. The associated symptoms are tumor formation and in severe conditions, development of acute myeloid leukemia.
Increased risks of BRCA mutation in ethnic groups
Certain ethical, geographical group or we can say population may have great frequency of having mutated BRCA gene compared to others. For instance, Jewish populations, Dutch and Icelandic populations have greater frequency of BRCA gene mutation. The reason behind this is still an area of research. However, one possible reason is intercultural marriages and history of BRCA mutation.
Inheritance pattern of BRCA gene
BRCA gene mutation passes on to offspring in autosomal dominant pattern which means that mutated gene even from one pattern can express itself and cause cancer development.
Genetic testing for identifying mutation
Second generation gene sequencing and genetic testing tools are available for identifying BRCA mutation in family. This helps to take preventive measures to prevent cancer development. For genetic testing, DNA is isolated either from blood sample or the saliva of the person. Lab analysis may take one to two weeks and even more for detailed sequencing and study.
The possible results of genetic testing
When genetic testing is performed for BRCA gene mutation analysis, the results can be positive, negative or ambiguous.
- Positive test results indicate that the individual has inherited mutation of BRCA genes. This significantly increases the chances of cancers related to this gene mutation. Each child of affected parent has 50% chances of mutation inheritance. Similarly, there are 50% chances that the siblings of affected person have BRCA gene mutation.
- Negative results are sometimes difficult to understand and elaborate. The reason is that the family history of the person matters in determining the risk factors and diagnosis. The true negative test is the one in which the person has no BRCA gene mutation and he/she cannot pass this gene mutation to next generation. However, if the person himself has no mutation but his/her close relatives have this mutation; the test results become vague and less clear. Therefore, there is possibility of harmful BRCA gene mutation but no identifiable by genetic testing.
- Ambiguous results show uncertainty of fact that whether the mutation is present or not. About 10% of cases show ambiguous results. For instance, the genetic testing identifies a gene change which have not been previously studied and found associated with breast cancer.
Genetic counseling helps a lot in case of positive and ambiguous results of genetic testing.
Negative aspect of genetic testing
Genetic testing may have some associated issues although not physically harmful. For instance, the person diagnosed with mutation may have stress, depression due to possibility of having breast or ovarian cancer in early age. Those with negative and ambiguous results may also have stress and fear of getting the disease. Some may have ‘survival guilt’ when they themselves have no mutation but a loved one such as sister or other have the mutation. Psychological assistance can help in many cases. One possible issue is disclosure of a person’s private information and data without his/her consent. For the purpose, the Health Insurance Portability and Accountability Act and Law protect the privacy of each individual going through genetic or clinical testing.
Managing risks of cancer with BRCA gene mutation
There are some strategies that help people to manage their risks of breast and related cancer to BRCA gene mutation. These strategies are:
- Prophylactic surgery
1. Enhance and regular Screening
Women with positive test result of BRCA gene mutation may opt for regular and enhanced screening of breast cancer at younger age. Breast cancer screening should start at age 25-30 year in young female. A mammogram of breast provides help in screening of breast to detect any tumor formation at initial stages. Moreover, magnetic resonance imaging or MRI is another option to locate and detect lump or tumor in breast. Health care organizations such as American Cancer Society suggest that the best option is to have an MRI as well as mammography annually.
Trans-vaginal ultrasound is another detection test for screening of ovarian cancer. Similarly, blood testing for CA-125 transcription factor also detects ovarian cancer at initial stages.
On the other hand, men with BRCA mutations should have regular screening test for breast cancer and prostate cancer.
2. Prophylactic surgery (reducing the risks factor)
This surgery involves removal of ‘at risk’ tissue which is breasts, ovaries and Fallopian tube in case of BRCA mutation. Removing Fallopian tube is necessary as mostly the cancer starts and spread from Fallopian tube cells. Secondly, removing ovaries prevents the chances of breast cancer as it lowers the hormonal production that is responsible for growth of cells including the cancerous cells in breast tissues.
Prophylactic surgery does not ensure 100% result as removal of all at-risk tissue is not possible. Therefore, the method reduces risks of cancer rather than completely preventing it. Unfortunately, some may develop the breast cancer even after the surgical removal or breast and ovaries.
The studies show that prophylactic removal surgery reduces the mortality rate by ovarian cancer by 80%. There is about 56% reduction of mortality rate due to breast cancer. Therefore, on the whole we can say that prophylactic surgery reduces the chances of cancer development as also the mortality rate due to breast and ovarian cancer.
However, this risk reducing factor has huge concerns and not easy to take by everyone, especially for women. For instance, removal of ovaries or breast at younger age itself brings social pressure, stress and depression in females.
3. Chemo prevention
As the name indicates, this strategy to maintain BRCA gene mutation and risk of cancer involves use of chemical drugs and medicines to reduce the risk factors for cancer. The food and drug administration FDA has approved such therapeutic medicines for preventing cancer development. These include tamoxifen and raloxifene which reduce the risks of breast cancer in young females with BRCA gene mutation. Studies also prove that these chemo preventive drugs reduce the risk of cancer in those with BRCA gene mutation.
Studies indicate that the oral contraceptive pills also lower the risks of developing the ovarian cancer in females.
Chemo prevention is probably the best solution to manage the risks factors in persons with BRCA gene mutation for those who do not choose the prophylactic surgery.
Recent advances in researches
Researches and lab trails are underway to find out and pinpoint the exact basis of breast cancer and ovarian cancer. The BRCA gene mutation is responsible for these cancer types. However, there can be more genes linked with onset of breast and ovarian cancer. Recently, researchers have identified few other genes namely PALB2, TP53, CHEK2 and STK1 genes which may contribute in breast cancer development. Once, the genetic locus for causing cancerous cells development is identified, this will be easier to target that point of mutation.
Targeted gene therapy for repairing or silencing the mutated gene is another area of research similar to gene therapy which involves replacement of mutated gene with normal one. This is to revive the function of protein production that a normal gene does in healthy individual.
Hopefully in future, there will be a best treatment option for breast and ovarian cancer as well as strategies to manage the risks of developing cancer in those people with BRCA gene mutation and inheritance.