BRCA mutation

BRCA mutation
Absolute risk of cancers in BRCA1 or BRCA2 mutation.[1]
Specialty	Medical genetics

A BRCA mutation is a mutation in either of the BRCA1 and BRCA2 genes, which are tumour suppressor genes. Hundreds of different types of mutations in these genes have been identified, some of which have been determined to be harmful, while others have no proven impact. Harmful mutations in these genes may produce a hereditary breast–ovarian cancer syndrome in affected persons. Only 5–10% of breast cancer cases in women are attributed to BRCA1 and BRCA2 mutations (with BRCA1 mutations being slightly more common than BRCA2 mutations), but the impact on women with the gene mutation is more profound.^[2] Women with harmful mutations in either BRCA1 or BRCA2 have a risk of breast cancer that is about five times the normal risk, and a risk of ovarian cancer that is about ten to thirty times normal.^[3] The risk of breast and ovarian cancer is higher for women with a high-risk BRCA1 mutation than with a BRCA2 mutation. Having a high-risk mutation does not guarantee that the woman will develop any type of cancer, or imply that any cancer that appears was actually caused by the mutation, rather than some other factor.

High-risk mutations, which disable an important error-free DNA repair process (homology directed repair), significantly increase the person's risk of developing breast cancer, ovarian cancer and certain other cancers. Why BRCA1 and BRCA2 mutations lead preferentially to cancers of the breast and ovary is not known, but lack of BRCA1 function seems to lead to non-functional X-chromosome inactivation. Not all mutations are high-risk; some appear to be harmless variations. The cancer risk associated with any given mutation varies significantly and depends on the exact type and location of the mutation and possibly other individual factors.

Mutations can be inherited from either parent and may be passed on to both sons and daughters. Each child of a

Biallelic and homozygous inheritance of a BRCA gene leads to a severe form of Fanconi anemia, and is embryonically lethal in the majority of the cases.

Health effects

Women with deleterious mutations in either the BRCA1 or BRCA2 genes have a high risk of developing breast and/or ovarian cancer. Because different studies look at different populations, and because different types of mutations have somewhat different risks, the risk is best expressed as a range, rather than a single number.^{[9]: 89–111}

Approximately 50% to 65% of women born with a deleterious mutation in BRCA1 will develop breast cancer by age 70, and 35% to 46% will develop ovarian cancer by age 70. Approximately 40% to 57% of women with a deleterious mutation in BRCA2 will develop breast cancer by age 70, and 13% to 23% will develop ovarian cancer by age 70.^{[9]: 89–111 [10]}

Women with a breast cancer associated with a BRCA mutation have up to a 40% probability of developing a new primary breast cancer within 10 years following initial diagnosis if they did not receive tamoxifen treatment or have an oophorectomy.^[4] The woman's ten-year risk for ovarian cancer is also increased by 6-12% under these conditions.^[4]

Statistics for BRCA-related ovarian cancer typically encompass not only cancer of the

BRCA-related breast cancer appears at an earlier age than sporadic breast cancer.[9]^: 89–111 It has been asserted that BRCA-related breast cancer is more aggressive than normal breast cancer, however most studies in specific populations suggest little or no difference in survival rates despite seemingly worse prognostic factors.^[11][12][13]

• BRCA1 is associated with triple-negative breast cancer, which does not respond to hormonal treatments and cannot be usefully treated with some drugs, such as trastuzumab. Breast cancer often appears about two decades earlier than normal.^{[9]: 89–111}
• BRCA2 is associated primarily with post-menopausal breast cancer, although the risk of pre-menopausal breast cancer is significant. It is typically highly responsive to hormonal treatments.^{[9]: 89–111}

BRCA-related ovarian and fallopian tube cancer is more treatable than average because it is unusually susceptible to platinum-based chemotherapy like cisplatin.^{[9]: 275–302} There are also FDA-approved maintenance therapies available in the form of PARP inhibitors.^[14] BRCA1-related ovarian cancer appears at younger ages, but the risk for women with BRCA2 climbs markedly at or shortly after menopause.^{[9]: 275–302}

Survival impact

A 25-year-old woman with no mutation in her BRCA genes has an 84% probability to reach at least the age of 70.^[15] Of those not surviving, 11% die from either breast or ovarian cancer, and 89% from other causes.

Compared to that, a woman with a high-risk BRCA1 mutation, if she had breast cancer screening but no prophylactic medical or surgical intervention, would have only 59% chance to reach age 70, twenty-five percentage points lower than normal. Of those women not surviving, 26% would die of breast cancer, 46% ovarian cancer, and 28% other causes.^[15]

Women with high-risk BRCA2 mutations, with screening but with no prophylactic medical or surgical intervention, would have only 71% chance to reach age 70, thirteen percentage points lower than normal. Of those not surviving, 21% would die of breast cancer, 25% ovarian cancer and 54% other causes.^[15]

The likelihood of surviving to at least age 70 can be improved by several medical interventions, notably prophylactic mastectomy and oophorectomy.^[15]

Male breast cancer

Men with a BRCA mutation have a dramatically elevated relative risk of developing breast cancer, but because the overall incidence of breast cancer in men is so low, the absolute risk is equal to or lower than the risk for women without a BRCA mutation.^[9]: Ch8 Approximately 1% to 2% of men with a BRCA1 mutation will develop breast cancer by age 70. Approximately 6% of men with a BRCA2 mutation will develop breast cancer by age 70, which is approximately equal to the risk for women without a BRCA mutation. Very few men, with or without a predisposing mutation, develop breast cancer before age 50.^[9]: Ch8

Approximately half of men who develop breast cancer have a mutation in a BRCA gene or in one of the other genes associated with hereditary breast–ovarian cancer syndromes.

Breast cancer in men can be treated as successfully as breast cancer in women, but men often ignore the signs and symptoms of cancer, such as a painful area or an unusual swelling, which may be no bigger than a grain of rice, until it has reached a late stage.^[9]: Ch8

Unlike other men, men with a BRCA mutation, especially a BRCA2 mutation, may benefit from professional and self

Melanoma is the most deadly skin cancer, although it is easily cured in the early stages. The normal likelihood of developing melanoma depends on race, the number of moles the person has, family history, age, sex, and how much the person has been exposed to UV radiation. BRCA2 mutation carriers have approximately double or triple the risk that they would normally have, including a higher than average risk of melanoma of the eye.^{[9]: Ch8 [16]}

Cancer of the

The dilemma of whether or not to have children may be a source of stress for women who learn of their BRCA mutations during their childbearing years.[18]

There is likely little or no effect of a BRCA gene mutation on overall fertility,^[19] although women with a BRCA mutation may be more likely to have primary ovarian insufficiency.^[20]

Each pregnancy in genetically typical women is associated with a significant reduction in the mother's risk of developing breast cancer after age 40.[18] The younger the woman is at the time of her first birth, the more protection against breast cancer she receives.^{[9]: 113–142} Breastfeeding for more than one year protects against breast cancer.^{[9]: 113–142} Pregnancy also protects against ovarian cancer in genetically typical women.^[18]

Although some studies have produced different results, women with BRCA mutations are generally not expected to receive these significant protective benefits.^{[9]: 113–142 [18]} Current research is too limited and imprecise to permit calculation of specific risks.^[18] However, the following general trends have been identified:

• For women with a BRCA1 mutation, the woman's age when she first gives birth has no association with her risk of breast cancer.^[18] Childbearing provides no protection against breast cancer, unless the woman has five or more full-term pregnancies, at which point she receives only modest protection.^[18] Similar to genetically typical women, pregnancy protects against ovarian cancer in BRCA1 women.^[18] Breastfeeding for more than one year significantly protects against breast cancer.^[18] This effect may be as high as 19% per year of breastfeeding, which is much higher than that seen among genetically typical women.^[25] The effect, if any, of long-term breastfeeding on ovarian cancer is unclear.^[18]
• For women with a BRCA2 mutation, each pregnancy is paradoxically associated with a statistically significant increase in the risk for breast cancer.^[18] Unlike genetically typical women or women with BRCA1 mutations, breastfeeding has no effect on either cancer in women with BRCA2 mutations.^[18] Limited and conflicting data suggest that, also unlike other women, pregnancy does not reduce ovarian cancer risk significantly in women with a BRCA2 mutation and might increase it.^[18]

Biallelic and homozygous inheritance

Reports of patients biallelic or homozygous for a deleterious BRCA allele conferring a greatly increased risk of breast cancer are rare. This is because deleterious BRCA alleles are

Both BRCA genes are

There are many variations in BRCA genes, and not all changes confer the same risks. [9]^: 39–50 Some variants are harmless; others are known to be very harmful. Some

• Deleterious mutation: The change is proven to cause significant risks. Often, these are frameshift mutations that prevent the cell from producing more than the first part of the necessary protein.
• Suspected deleterious: While nothing is proven, the variation is currently believed to be harmful.
• Variant of uncertain significance (VUS): Whether the change has any effect is uncertain. This is a common test result, and most variations began in this category. As more evidence is acquired, these are re-classified.
• Variant, favor polymorphism: While nothing is proven, the variation is currently believed to be harmless.
• Benign polymorphism: The change is classified as harmless. These may be reported as "no mutation".

Deleterious mutations have high, but not complete, genetic penetrance, which means that people with the mutation have a high risk of developing disease as a result, but that some people will not develop cancer despite carrying a harmful mutation.

Diagnosis

Genetic counseling is recommended in women whose personal or family health history suggests a greater than average likelihood of a mutation.^[31] The purpose of genetic counseling is to educate the person about the likelihood of a positive result, the risks and benefits of being tested, the limitations of the tests, the practical meaning of the results, and the risk-reducing actions that could be taken if the results are positive. They are also trained to support people through any emotional reactions and to be a neutral person who helps the client make his or her own decision in an informed consent model, without pushing the client to do what the counselor might do. Because the knowledge of a mutation can produce substantial anxiety, some people choose not to be tested or to postpone testing until a later date.^{[9]: 51–74}

Relative

• A known mutation (BRCA1 or BRCA2) in a cancer susceptibility gene within the family
• Women affected by any breast cancer diagnosed under the age of 30^[33]
• Women affected by triple negative breast cancer (TNBC) (
  HER2/neu
  negative) under the age of 50
• Two relatives (FDR/SDR) diagnosed under the age of 45
• Three relatives (FDR/SDR) diagnosed with average age of 50 or less
• Four relatives at any ages
• Ovarian cancer with either an additional diagnosed relative or a relative with male breast cancer
• A single family member with both breast and ovarian cancer
• Male breast cancer
• Pancreatic cancer with breast or ovarian cancer in the same individual or on the same side of the family
• Ashkenazi Jewish, Filipino, or Polish ancestry with one FDR family member affected by breast or ovarian cancer at any age^[34]

Testing young children is considered medically unethical because the test results would not change the way the child's health is cared for.^{[9]: 82–85}

Test procedure

Two types of tests are available.

Testing is commonly covered by health insurance and public healthcare programs for people at high risk for having a mutation, and not covered for people at low risk.^{[9]: 51–74} The purpose of limiting the testing to high-risk people is to increase the likelihood that the person will receive a meaningful, actionable result from the test, rather than identifying a variant of unknown significance (VUS). In Canada, people who demonstrate their high-risk status by meeting specified guidelines are referred initially to a specialized program for hereditary cancers, and, if they choose to be tested, the cost of the test is fully covered. In the US in 2010, single-site testing had a retail cost of US$400 to $500, and full-length analysis cost about $3,000 per gene, and the costs were commonly covered by private health insurance for people deemed to be at high risk.

The test is ordered by a physician, usually an

A positive test result for a known deleterious mutation is proof of a predisposition, although it does not guarantee that the person will develop any type of cancer. A negative test result, if a specific mutation is known to be present in the family, shows that the person does not have a BRCA-related predisposition for cancer, although it does not guarantee that the person will not develop a non-hereditary case of cancer. By itself, a negative test result does not mean that the patient has no hereditary predisposition for breast or ovarian cancer. The family may have some other genetic predisposition for cancer, involving some other gene.[9]^: 89–111

Cancer prevention

A variety of screening options and interventions are available to manage BRCA-related cancer risks. Screenings are adjusted to individual and familial risk factors.^{[citation needed]}

As these screening methods do not prevent cancer, but merely attempt to catch it early, numerous methods of prevention are sometimes practiced, with varying results.^{[9]: 175–207}

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.^{[9]: 175–207}

Breast imaging studies usually include a

Aromatase inhibitors are medications that prevent estrogen production in the adrenal glands and adipose tissue. They have fewer side effects than selective estrogen receptor modulators like tamoxifen, but do not work in premenopausal women, because they do not prevent the ovaries from producing estrogen.^{[9]: 113–142}

Surgery

Several type of preventive surgeries are known to substantially reduce cancer risk for women with high-risk BRCA mutations.^[40] 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. Surgeries such as mastectomy and oophorectomy do not eliminate the chance of breast cancer; cases have reportedly emerged despite these procedures.^[41]

• Tubal ligation is the least invasive of these surgeries and appears to reduce ovarian cancer risk for BRCA1 carriers by over 60%. Salpingectomy is another option which is more invasive than tubal ligation and may result in additional risk reduction. Both of these can be performed anytime after childbearing is complete.^[40] Unlike other prophylactic surgeries, these two surgeries do not reduce the risk of breast cancer.^[42]
• Prophylactic (preventive) mastectomy
  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 has no direct effect on BRCA-related cancers, but it enables the women to use some medications that reduce breast cancer risk (such as tamoxifen) with the risk of uterine cancer and to use fewer hormones to manage the adverse effects of a prophylactic oophorectomy.

Whether and when to perform which preventive surgeries is a complex personal decision. Current medical knowledge offers some guidance about the risks and benefits. 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. Different people also have different values. They may choose to focus on total cancer prevention, psychological benefits, current quality of life, or overall survival. The possible impact of future medical developments in treatment or prognosis may also be of some importance for very young women and family planning. The decision is individualized and is usually based on many factors, such as earliest occurrence of BRCA-related cancer in close relatives.

An increasing number women who test positive for faulty BRCA1 or BRCA2 genes choose to have risk-reducing surgery. At the same time the average waiting time for undergoing the procedure is two-years which is much longer than recommended.^[43][44]

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. The risk of ovarian cancer is low before this age, and the negative effects of oophorectomy are less serious as the woman nears natural menopause.^[15][45]

• For carriers of high-risk BRCA1 mutations, prophylactic oophorectomy around age 40 reduces the risk of ovarian and breast cancer and provides a substantial long-term survival advantage. Having this surgery at a very young age provides little or no additional survival advantage, but it does increase the adverse effects from the surgery. Compared to no intervention, having this surgery around age 40 increases the woman's chance of reaching age 70 by fifteen percentage points, from 59% to 74%. Adding prophylactic mastectomy increases the expected survival by several more percentage points.
• For carriers of high-risk BRCA2 mutations, oophorectomy around age 40 has a smaller effect. The surgery increases the woman's chance of reaching age 70 by only five percentage points, from 75% to 80%. When only preventive mastectomy is done at age 40 instead, the improvement is similar, with the expected chance rising from 75% to 79%. Doing both surgeries together around age 40 is expected to improve the woman's chance of reaching age 70 from 75% to 82%

For comparison, women in the general population have an 84% chance of living to age 70.

Research has looked into the effects of risk-reducing surgery on the psychological and social wellbeing of women with a BRCA mutation.^[46] Due to limited evidence, a 2019 meta analysis was unable to draw conclusions on whether interventions can help with the psychological effects of surgery in female BRCA carriers. More research is needed to conclude how best to support women who choose surgery.^[46]

Mastectomy

In a woman who has not developed breast cancer, removing the breasts may reduce her risk of ever being diagnosed with breast cancer by 90%, to a level that is approximately half the average woman's risk.^{[9]: 209–244}

Bilateral mastectomy is the removal of both breasts by a

• Simple mastectomy, which is recommended for women not having breast reconstruction, leaves the least amount of breast tissue in the body and therefore achieves the greatest risk reduction. In addition to prophylactic use, it is also used by women who have been diagnosed with earlier stages of cancer.
• Skin-sparing mastectomy removes the tissue of the breast, nipple, and areola, but leave the "excess" skin in place for reconstruction. It has less visible scar tissue than a simple mastectomy.
• Nipple-sparing mastectomy removes the breast tissue, but leaves the nipple and the areola intact for a more natural appearance.
• Subcutaneous mastectomy removes the breast tissue, but leaves the nipple and areola intact. The scars are hidden in the inframammary fold
  under the breast.
• Areola-sparing mastectomy removes the breast tissue and the nipple, but not the areola.
• Nerve-sparing mastectomy is an effort to maintain the nerves that provide sensation to the skin over the breasts. Breasts that have undergone any of these surgeries have much less tactile sensation than natural breasts. Nerve-sparing techniques are an effort to retain some feeling in the breasts, with limited and often only partial success.^{[9]: 209–244}

Which technique is used is determined by the existence of any cancer and overall health, as well as by the woman's desire, if any, for

BRCA2 related ovarian cancer tends to present in perimenopausal or menopausal women, so salpingo-oophorectomy is recommended between ages 45 and 50.[9]^{: 275–302}

The surgery is often done in conjunction with a

Some sources assume that oophorectomy before age 50 doubles the risk of cardiovascular disease and increases risk of hip fractures caused by osteoporosis in the relevant population.[15]

Non-medical choices

Given the high risks and the low benefit of lifestyle choices in BRCA mutation carriers, no lifestyle choices provide sufficient protection.^{[9]: 113–142}

Having her first child at a younger age, having more children than average, and breastfeeding for more than one year decreases the risk of breast cancer for an average-risk woman.^{[9]: 113–142} Studies about this effect among BRCA mutation carriers have produced conflicting results, but generally speaking, having children is believed to provide little or no protection against breast cancer for women with BRCA1 mutations, and to paradoxically increase the risk of breast cancer for women with BRCA2 mutations.^{[9]: 113–142 [18]}

Being physically active and maintaining a healthy body weight prevents breast and other cancers in the general population, as well as preventing heart disease and other medical conditions. Among women with a BRCA mutation, being physically active and having had a healthy body weight as an adolescent has no effect on ovarian cancer and delays, but does not entirely prevent, breast cancer after menopause.^{[9]: 113–142 [47]} In some studies, only significant, strenuous exercise produced any benefit.^{[9]: 113–142} Obesity and weight gain as an adult are associated with breast cancer diagnoses.^{[9]: 113–142}

Studies on specific foods, diets, or

In a study conducted with Ashkenazi Jewish women, it was observed that mutation carriers born before 1940 have a much lower risk of being diagnosed with breast cancer by age 50 than those born after 1940; this was also observed in the non-carrier population.[47] The reasons for the difference is unknown. Unlike the general population, age at menarche and age at menopause has no effect on breast cancer risk for BRCA mutation carriers.^{[9]: 113–142}

Evolutionary advantage

Studies have shown that BRCA1 mutations are not random, but under adaptive selection, indicating that although BRCA1 mutations are linked to breast cancer, the mutations likely have a beneficial effect as well.^[48]

Patents

A patent application for the isolated

According to an article published in the journal, Genetic Medicine, in 2010, "The patent story outside the United States is more complicated.... For example, patents have been obtained but the patents are being ignored by provincial health systems in Canada. In Australia and the UK, Myriad's licensee permitted use by health systems, but announced a change of plans in August 2008. ... Only a single mutation has been patented in Myriad's lone European-wide patent, although some patents remain under review of an opposition proceeding. In effect, the United States is the only jurisdiction where Myriad's strong patent position has conferred sole-provider status."[50]^[51] Peter Meldrum, CEO of Myriad Genetics, has acknowledged that Myriad has "other competitive advantages that may make such [patent] enforcement unnecessary" in Europe.^[52]

Legal decisions surrounding the BRCA1 and BRCA2 patents will affect the field of genetic testing in general.^[53] In June 2013, in Association for Molecular Pathology v. Myriad Genetics (No. 12-398), the US Supreme Court unanimously ruled that, "A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated," invalidating Myriad's patents on the BRCA1 and BRCA2 genes. However, the Court also held that manipulation of a gene to create something not found in nature could still be eligible for patent protection.^[54]

See also

• Medical genetics of Jewish people
• SEE-FIM Protocol

References