Impact+on+Patients+Who+Test+Positive+for+BRCA1+and+BRCA2+Gene+Mutation

Introduction
A person who finds that their family has certain genetic mutations might have themselves tested to determine if they have this same mutation. In the case of breast cancer, we know that the mutations in the BRCA1 and BRCA2 genes greatly increase the patient's probability of developing breast cancer. Once tested, the patient is presented with various treatment options depending on their test result. A patient may test positively or negatively for these results, and may even have an ambiguous test result in some cases.

What is Breast Cancer?
Breast cancer or malignant breast neoplasm originates from breast tissue. The two types of breast cancer are ductal carcinomas and lobular carcinomas, depending on where in the breast they are found. Signs of breast cancer are lumps, changes in size or shape of the breast, nipple discharge, redness, and scaling. The size, rate of growth, and other characteristics of the tumor determines the kind of treatment often including surgery, chemotherapy, and radiation.

What are BRCA1 and BRCA2?
The genes stand for Breast Cancer Gene 1 and 2. The BRCA1 and BRCA2 genes are present in all genomes. The genes are known as [|tumor suppressor genes]because they prevent uncontrolled cell growth and maintain the genomic integrity by acting as DNA repair proteins. When mutated, this prevention is stopped and a patient's risk of developing breast cancer is greatly increased. Figure 1: Location of BRCA1 gene on Chromosome 17 and BRCA1 protein created by Pymol protein data bank.

Function of BRCA1 AND BRCA2
In an experiment, patients were treated with [|hydroxyurea], a drug that stalls replication forks in the S phase of DNA replication. At these stalled forks, scientists found accidental breaks in unreplicated single strands of DNA. Normally, this is repaired by homology-directed repair, or HDR. In normal cells, BRCA1 molecules are evenly distributed throughout the nucleus. However, when a patient is exposed to hydroxyurea, scientists noticed that BRCA1 molecules tended to change location in the nucleus and clustered around the replication forks amongst other DNA repair proteins (BRCA2 among them). This was the first indication that BRCA1 and BRCA2 were involved in DNA repair (and therefore are tumor suppressor genes). Scientists began breaking single strands of DNA with laser beams, and found that BRCA proteins tended to localize at this breakage. Mice who were experimentally deprived of BRCA1 function quickly died, while those denied BRCA2 function showed an increase in the fusion of non homologous chromosomes, a common side effect of the lack of single strand DNA repair. Scientists also cultured cells that contained single strand DNA breaks, and concluded that they reached cell death in the absence of BRCA1 and BRCA2 function. All of this experimentation led to the conclusion that BRCA1 and BRCA2 are involved in the repair of damaged DNA. BRCA1 and BRCA2 function as tumor suppressor genes, and are involved in the regulation of DNA repair through the process of homologous recombination (a means of double strand DNA repair). A protein called RAD51 is a key protein in HDR (homology derived repair), which must bind to BRCA in order to be successful. While it remains unknown exactly who the BRCA genes function in normal cells, it is clear that in their absence, DNA repair is not accomplished through homology derived repair, and tumor proliferation is influenced greatly.

Testing for Genetic Mutations
The American Society of Cancer recommends that genetic testing for cancerous mutations occur only when an individual has a strong family history of cancer, the test can be properly interpreted, and the test will "influence medical management." Strong family history indicates not only the number of family members affected, but also the age at which certain members were diagnosed. Patients typically have [|genetic counseling]before and after genetic testing. A health care professional will inform potential patients of the benefits and risks of each result (see below). In order to test for genetic mutations, blood must be drawn from the patient. This can be done in a doctors office, hospital, or clinic and then sent to a laboratory which specializes in genetic testing. There are a number of ways to asses for mutations in BRAC1 and BRAC2; the most common way involves analyzing whether or not the proteins produced by these two genes are abnormal. Testing can cost from hundreds to thousands of dollars which it not always covered by insurance.

Concerns with Testing
A recent [|study] states about one in four women who are eligible for BRCA testing don't get the test due to concerns with cost, discrimination, and confidentiality. Other reasons why people have concerns with testing include...


 * ====How the results might affect your relationships. One has to decide if you would tell a family member who then has to decide if they want to have the test.====
 * ====Your insurance does not cover the testing, or covers only some of it. Genetic testing can be very expensive (several hundred to several thousand dollars).====
 * ====Having difficult emotions. One may be afraid and anxious if you test positive or guilty if one tests negative and someone in your family tests positive.====
 * ====Genetic discrimination if authorities gain access to information about genetic mutations, causing issues with employment and insurance.

Figure 2: Results from study which shows amount of women who underwent or declined BRCA testing.

Test Results
Positive

Negative

Ambiguous

Statistics
It is important to remember that 90-95% of breast cancers are not associated with a BRCA mutation and therefore a negative test result doesn't mean the patient will not develop breast cancer. A woman will have about a 10-13% chance of developing breast cancer even without these genetic mutations. Yet if just one of these genes (either BRAC1 or BRAC2) are altered, a womans risk is increased to 50-85%. It is 3 to 7 times more likely that a person who tested positively will develop cancer, so it is important for those with a family history to be tested. Also, a patients lifetime risk of ovarian cancer is significantly elevated as well: 16% to 60%, versus just under 2% for the general population. A genetic testing [|study] found that out of those who tested positive, 35% of women considered a prophylactic mastectomy and prophylactic oophorectomy was considered an important option by 76%. 25% of both BRCA1 positive and negative individuals were concerned about discrimination by insurance companies. 80% of those who tested negative reported emotional relief, whereas one-third of those who tested positive were reported having sadness, anger, or guilt.

BRCA1 protein and obesity
A recent [|study] done by [|The National Cancer Institute](NCI) has found a link between the BRCA1 protein and obesity. The C-terminal binding protein (CtBP) acts to control the BRCA gene in rapidly growing cells by responding to the metabolic state- how cells use and store energy. Obese people have an "energy imbalance" which means the cells store a high amount of energy. This caused CtBP activity to increase which therefore decreases BRCA1 protein. When they decreased the levels of CtBP they could recover the BRCA1 protein.

Summary
For a women who decides to undergo genetic testing, it is important to keep in mind that the results are simply a "risk assessment." Results are not a guarantee, and this needs to be taken into account in the case of any result. It is imperative that a woman contemplate all her options and weigh the benefits and the risks, while assessing the toll her actions may take not only on herself, but also on her close family members. Each course of action is a personal decision, individual to each particular patient. While those in the medical field continue to explore and experiment with further preventative measures to evade breast cancer for these patients, we must utilize the options currently available in hope of attaining survival and high quality of life for all patients who undergo genetic testing.