BRCA mutations

BRCA1 and BRCA2 (Pic. 1) are normally expressed in the cells of breast and other tissue, where they help repair damaged DNA, or destroy cells if DNA cannot be repaired. They are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double-strand breaks. 

If BRCA1 or BRCA2 itself is damaged by a BRCA mutation, damaged DNA is not repaired properly, and this increases the risk for breast cancer. Thus, although the terms "breast cancer susceptibility gene" and "breast cancer susceptibility protein" describe a proto-oncogene (a normal gene that could become an oncogene due to mutations or increased expression), BRCA1 and BRCA2 are normal; it is their mutation that is abnormal. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation.

Certain variations of the BRCA1 gene lead to an increased risk for breast cancer as part of a hereditary breast-ovarian cancer syndrome. Researchers have identified hundreds of mutations in the BRCA1 gene, many of which are associated with an increased risk of cancer. The lifetime risk of breast cancer in BRCA1- and BRCA2-mutation carriers is 45–80%. The lifetime risk of ovarian cancer is 45–60% for BRCA1-mutation carriers and 11–35% for BRCA2-mutation carriers. In the general population, a woman’s lifetime risk of breast cancer is 1 in 8, and the risk of ovarian cancer is 1 in 70. A number of studies examining the incidence of breast cancer have reported a lower likelihood amongst BRCA2-mutation carriers compared to BRCA1-mutation carriers. 

A woman with a BRCA mutation has a 20% chance of developing breast cancer by the time she is 40 years old. However, the risk increases to 37% by the age of 50, 55% by the age of 60, and is over 70% by the age of 70. For BRCA1-mutation carriers, the risk of ovarian cancer rises sharply in the 4th decade of life and then increases progressively by approximately 10% with each subsequent decade of life.

Symptoms

The first noticeable symptom of breast cancer is typically a lump that feels different from the rest of the breast tissue. More than 80% of breast cancer cases are discovered when the woman feels a lump. Indications of breast cancer other than a lump may include thickening different from the other breast tissue, one breast becoming larger or lower, a nipple changing position or shape or becoming inverted, skin puckering or dimpling, a rash on or around a nipple, discharge from nipple/s, constant pain in part of the breast or armpit, and swelling beneath the armpit or around the collarbone.

The most typical symptoms of ovarian cancer include bloating, abdominal or pelvic pain or discomfort, back pain, irregular menstruation or postmenopausal vaginal bleeding, pain or bleeding after or during sexual intercourse, difficulty eating, loss of appetite, fatigue, diarrhea, indigestion, heartburn, constipation, nausea, early satiety, and possibly urinary symptoms (including frequent urination and urgent urination); typically these symptoms are caused by a mass pressing on the other abdominopelvic organs or from metastases.

Associated diseases

Women with deleterious mutations in these genes (BRCA1 and BRCA2) increase considerably an estimated cumulative lifetime risk for developing particularly breast and ovarian cancers. Deleterious mutations in both genes also increase the lifetime risks of ovarian cancer. 

Individuals who have a known BRCA mutation are also at risk for other malignancies. Approximately 30% of women with Fallopian tube cancer have a mutation in BRCA1 or BRCA2. In addition, the inheritance of a BRCA1 mutation has been linked with an increased risk of endometrial, pancreatic, and prostate cancer. A BRCA1 mutation has been shown to be associated with an increased risk of early onset colon cancer in a defined population but does not seem to increase the overall risk of colon cancer. Patients with a BRCA2 mutation have an increased risk of prostate and pancreatic cancer. 

Complications

• breast cancer
• ovarian cancer
• endometral cancer
• Fallopian tube cancer
• pancreatic cancer
• prostate cancer

Risk factors

Factors that aid in predicting whether a mutation has been inherited by a woman with breast cancer include the number of breast and/or ovarian cancer patients in the family, the age of diagnosis, her ancestry and various pathological features of the breast cancer.

Prevention

Identifying patients that should be considered for genetic testing is an important aspect of practice that is often overlooked. Pedigree analysis can be used in conjunction with available risk assessment models to determine whether a family is suspected of having hereditary, familial, or sporadic cancer. BRCA1 or BRCA2 gene mutations are inherited in an autosomal dominant fashion (Pic.2). The scoring system is a risk assessment model which may be applied to evaluate an individual’s risk of having a BRCA1 or BRCA2 mutation. The scoring system considers the age of cancer diagnosis as well as a family history of female breast, male breast, ovarian, prostate, and pancreatic cancer in the risk stratification model.
Specific criteria for referral for genetic testing vary amongst institutions but are all based on clinical characteristics that increase one’s chance of developing a hereditary breast and/or ovarian cancer. 

There are several different types of prevention of breast and ovary cancer:

• screening
• prophylactic surgery
• chemoprophylaxis

Screening

An intensive cancer screening regimen is usually advised for women with deleterious or suspected deleterious BRCA mutations in order to detect new cancers as early as possible. A typical recommendation includes frequent breast cancer screening as well as tests to detect ovarian cancer.

Breast imaging studies usually include a breast MRI (magnetic resonance imaging) once a year, beginning between ages 20 and 30, depending on the age at which any relatives were diagnosed with breast cancer. Mammograms (the process of using low-energy X-rays to examine the human breast) (Pic. 3) are typically used only at advanced age as there is reason to believe that BRCA carriers are more susceptible to breast cancer induction by X-ray damage than general population. 

Alternatives include breast ultrasonography, CT scans (computed tomography), PET scans(positron emission tomography), scintimammography, elastography, thermography, ductal lavage, and experimental screening protocols, some of which hope to identify biomarkers for breast cancer (molecules that appear in the blood when breast cancer begins).

Ovarian cancer screening usually involves ultrasonography of the pelvic region, typically twice a year. Women may also use a blood test for CA-125 (a tumor marker or biomarker that may be elevated in the blood of some patients with specific types of cancers) and clinical pelvic exams. The blood test has relatively poor sensitivity and specificity for ovarian cancer. 

In both breast and ovarian screening, areas of tissue that look suspicious are investigated with either more imaging, possibly using a different type of imaging or after a delay, or with biopsies of the suspicious areas.

Prophylactic surgery

Several type of preventive surgeries are known to substantially reduce cancer risk for women with high-risk BRCA mutations. The surgeries may be used alone, in combination with each other, or in combination with non-surgical interventions to reduce the risk of breast and ovarian cancer. Mastectomy and oophorectomy do not completely eliminate the chance of breast cancer; cases have reportedly emerged despite these procedures. 

• Tubal ligation (fallopian tubes are clamped and blocked or severed and sealed) is the least invasive of these surgeries and appears to reduce ovarian cancer risk for BRCA1 carriers by over 60%. 
• Salpingectomy (surgical removal of a Fallopian tube) is another option which is more invasive than tubal ligation and may result in additional risk reduction. Unlike other prophylactic surgeries, these two surgeries do not reduce the risk of breast cancer.
• Prophylactic (preventive) mastectomy (surgical removal of one or both breasts, partially or completely) (Pic. 4) is associated with small risks and a large drop in breast cancer risk.
• Prophylactic salpingo-oophorectomy (removal of the ovaries and Fallopian tubes) results in a very large reduction in ovarian cancer risk, and a large reduction in breast cancer risk if performed before natural menopause. However, it also comes with the risk of substantial adverse effects if performed at a young age.
• Hysterectomy (surgical removal of the uterus) has no direct effect on BRCA-related cancers, but it enables the women to use some medications that reduce breast cancer risk with the risk of uterine cancer and to use fewer hormones to manage the adverse effects of a prophylactic oophorectomy.

Even carriers of the same mutation or from the same family may have substantially different risks for the kind and severity of cancer they are likely to get, as well as the age at which they may get them. The decision is individualized and is usually based on many factors, such as earliest occurrence of BRCA-related cancer in close relatives.

The protective effect of prophylactic surgery is greater when done at young age; however, oophorectomy also has adverse effects that are greatest when done long before natural menopause. For this reason, oophorectomy is mostly recommended after age 35 or 40, assuming childbearing is complete

Chemoprophylaxis 

• Tamoxifen
  Tamoxifen is a selective estrogen receptor modulator that has an inhibitory effect on estrogen receptors in breast tissue and a proliferative effect in the endometrium. BRCA-mutation carriers may be offered tamoxifen for primary prevention of breast cancer.
• Raloxifene
  Raloxifene is a selective estrogen receptor modulator, which is used primarily for the prevention of osteoporosis. The advantages of raloxifene are that it is as effective as tamoxifen in reducing the risk of invasive breast cancer while having a lower risk of thromboembolic events and a trend towards a lower risk of uterine cancer. 
• Oral Contraceptive Pill (OCP)
  OCP use has been found to have different effects on the lifetime risk of ovarian and breast cancer. It has generally been accepted that OCP use decreases one’s risk of ovarian cancer. However, much debate has ensued on whether the OCP increases one’s risk of developing breast cancer.
  

The dilemma of whether or not to have children is a significant source of stress for women who learn of their BRCA mutations during their childbearing years. 

There is little effect of a BRCA gene mutation on overall fertility, although women with a BRCA mutation may be more likely to have primary ovarian insufficiency ( the loss of function of the ovaries before age 40). Furthermore, women with an inherited BRCA1 mutation undergo menopause prematurely. Since BRCA1 is a key DNA repair protein, these findings suggest that naturally occurring DNA damages in oocytes are repaired less efficiently in women with a BRCA1 defect, and that this repair inefficiency leads to early reproductive failure.

BRCA mutation carriers may be more likely to give birth to girls than boys, however this observation has been attributed to ascertainment bias. 

If both parents are carriers of a BRCA mutation, then pre-implantation genetic diagnosis is sometimes used to prevent the birth of a child with BRCA mutations. Inheriting two BRCA1 mutations (one from each parent) has never been reported and is believed to be a lethal birth defect. Inheriting one BRCA1 mutation and one BRCA2 mutation has been reported occasionally; the child's risk for any given type of cancer is the higher risk of the two genes (e.g., the ovarian cancer risk from BRCA1 and the pancreatic cancer risk from BRCA2). Inheriting two BRCA2 mutations produces Fanconi anemia (most often acute myelogenous leukemia).