BRCA mutation
Encyclopedia
A BRCA mutation is a mutation in either of the genes BRCA1
and BRCA2
. Harmful mutations in these genes produce a hereditary breast-ovarian cancer syndrome in affected families. Mutations in BRCA1 and BRCA2 are uncommon, and breast cancer is relatively common, so these mutations consequently account for only five to ten percent of all breast cancer cases in women.
Hundreds of different types of mutations in these genes have been identified. High-risk mutations, which disable an important error-free DNA repair process, significantly increase the person's risk of developing breast cancer
, ovarian cancer
and other cancers. 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.
Women with harmful mutations in either BRCA1 or BRCA2 have 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. BRCA1 mutations typically confer a higher risk of breast and ovarian cancer in women than BRCA2 mutations. Having a high-risk mutation does not guarantee that the woman will develop any type of cancer, or guarantee that any cancer that appears was actually caused by the mutation, rather than some other factor, like alcohol consumption
.
Mutations can be inherited from either parent and may be passed on to both sons and daughters. Each child of a genetic carrier
, regardless of sex, has a 50% chance of inheriting the mutated gene from the parent who carries the mutation. As a result, half of the people with BRCA gene mutations are male. The risk of BRCA-related breast cancers for men with the mutation is higher than for other men, but still low. However, BRCA mutations can increase the risk of other cancers, such as colon cancer, pancreatic cancer
, and prostate cancer
.
s that produce proteins that are used by the cell in an enzymatic pathway that makes very precise, perfectly matched repairs to DNA molecules that have double-stranded breaks. The pathway requires proteins produced by several other genes, including CHEK2
, FANCD2
and ATM. Harmful mutations in any of these genes disable the gene or the protein that it produces.
The cancer risk caused by BRCA1 and BRCA2 mutations are inherited in a dominant fashion. A mutated BRCA gene can be inherited from either parent. Because they are inherited from the parents, they are classified as hereditary or germline mutation
s rather than acquired or somatic mutations. Cancer caused by a mutated gene is a hereditary cancer rather than a sporadic cancer.
Because humans have a diploid genome, each cell has two copies of the gene (one from each biological parent). Typically only one copy contains a disabling, inherited mutation, so the affected person is heterozygous for the mutation. If the functional copy is harmed, however, then the cell is forced to use alternate DNA repair mechanisms, which are more error-prone. The loss of the functional copy is called loss of heterozygosity
(LOH). Any resulting errors in DNA repair may result in cell death or a cancerous transformation of the cell.
There are many variations in BRCA genes, and not all changes confer the same risks. Some variants are harmless; others are known to be very harmful. Some single nucleotide polymorphism
s may confer only a small risk, or may only confer risk in the presence of other mutations or under certain circumstances. In other cases, whether the variant is harmful is unknown. Variants are classified as follows:
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.
is commonly recommended to people whose personal or family health history suggests a greater than average likelihood of a mutation. Genetic counselors are allied health professionals who are trained to explain genetics to people; some of them are also licensed as registered nurse
s or social workers. A medical geneticist is a physician who specializes in genetics. 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.
If the client chooses to be tested, then two types of tests are available. Both commonly use a blood sample
, although testing can be done on saliva. The quickest, simplest, and lowest cost test uses positive test results from a blood relative and checks only for the single mutation that is known to be present in the family. If no relative has previously disclosed positive test results, then a full test that checks the entire sequence of both BRCA1 and BRCA2 can be performed. In some cases, ethnicity can be used to narrow the testing to quickly check for common founder mutation
s. For example those with Jewish descent may be tested for the three most common mutations seen among Ashkenazi Jews
.
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. 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 USA 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 oncologist, and the results are always returned to the physician, rather than directly to the patient. How quickly results are returned depends on the test—single-site analysis requires less lab time—and on the infrastructure in place. In the USA, test results are commonly returned within one to several weeks; in Canada, patients commonly wait for eight to ten months for test results.
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.
Testing young children is considered medically unethical
because the test results would not change the way the child's health is cared for. Because taking birth control pills before age 20 is associated with very early development of breast cancer in BRCA mutation carriers, teenage girls may need to be tested before deciding to take hormonal contraceptives for any reason.
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.
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.
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 oopherectomy. The woman's ten-year risk for ovarian cancer is also increased by 6-12% under these conditions.
Statistics for BRCA-related ovarian cancer typically encompass not only cancer of the ovaries themselves, but also peritoneal cancer and the very rare, but somewhat easier to detect, cancer of the Fallopian tube
s. Women with a BRCA mutation have more than 100 times the normal rate of Fallopian tube cancer. These three types of these cancers can be difficult to distinguish in their advanced stages.
BRCA-related ovarian and Fallopian tube cancer is more treatable than average because it is unusually susceptible to platinum-based chemotherapy like cisplatin
. BRCA1-related ovarian cancer appears at younger ages, but the risk for women with BRCA2 climbs markedly at or shortly after menopause.
|+ Among women who die before age 70...
|- align="center"
| A 25-year-old woman with no mutation in her BRCA genes has an 84% probability to reach at least the age of 70. 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.
Women with high-risk BRCA2 mutations, with screening but with no prophylactic medical or surgical intervention, would have only 75% chance to reach age 70, nine percentage points lower than normal. Of those not surviving, 21% would die of breast cancer, 25% ovarian cancer and 54% other causes.
The likelihood of surviving to at least age 70 can be improved by several medical interventions, notably prophylactic mastectomy and oophorectomy.
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. 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.
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.
Unlike other men, men with a BRCA mutation, especially a BRCA2 mutation, may benefit from professional and self breast exams. Medical imaging is not usually recommended, but because male BRCA2 carriers have a risk of breast cancer that is very similar to the general female population, the standard annual mammogram program can be adapted to these high-risk men.
regimen is usually advised for women with deleterious or suspected deleterious BRCA mutations. A typical recommendation includes frequent breast cancer screening
as well as tests to detect ovarian cancer.
Breast imaging studies usually include a mammogram once a year, beginning between ages 20 and 30, depending on the age at which any relatives were diagnosed with breast cancer. Breast MRI
s (magnetic resonance imaging
) are typically also performed once per year, six months after the mammogram. Breast MRIs use a contrast medium
to enhance the image, and are far more expensive than mammograms. Mammograms, which are X-ray
s of the breast, expose the patient to some ionizing radiation
, and BRCA mutations make the person somewhat more likely to develop radiation-induced cancers, so they may be used less frequently in younger carriers. However, the risk-benefit analysis
shows that annual mammograms are appropriate. Both tests are commonly conducted because they each have strengths and weaknesses. Mammograms are better at identifying calcium microdeposits that are characteristic of some precancerous tissue changes. MRIs show more details in women with dense breast tissue, but the false positive rate (the tissue is actually healthy, but MRI suggests that cancer may be present) can be as high as 50%. Additionally, clinical breast exams and breast self-exams, which do not save lives in the general, asymptomatic population, are appropriate for women with BRCA mutations.
Alternatives include breast ultrasonography, CT scans, PET scans, 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
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.
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.
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.
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.
For comparison, women in the general population have an 84% chance of living to age 70.
Bilateral mastectomy is the removal of both breasts by a breast surgeon. The modified radical mastectomy is only used in women diagnosed with invasive breast cancer. Techniques for prophylactic mastectomies include:
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 breast reconstruction surgery for aesthetic purposes. Women who choose a flat-chested appearance or use external breast prostheses typically choose simple mastectomy, with its greater risk reduction.
Breast reconstruction is usually done by a plastic surgeon, and may be started as part of the same multi-hour surgery that removes the breasts. Multiple techniques for reconstruction have been used, with different locations and amounts of scarring. Some techniques use tissue from another part of the body, such as fat tissue from the lower abdomen or occasionally muscles from other parts of the torso. Others use breast implants, possibly preceded by tissue expanders, to provide volume. Some reconstruction techniques require multiple surgeries. Afterwards, some women have tattoo
s added to simulate breast areolas or have the skin reshaped to form a nipple.
(surgical removal of the ovaries) and salpingectomy
(surgical removal of the Fallopian tubes) are strongly recommended to women with BRCA mutations. Salpingo-oophorectomy is the single most effective method of preventing ovarian and Fallopian tube cancer in women with a BRCA mutation. However, a small risk of primary peritoneal cancer
remains, at least among women with BRCA1 mutations, since the peritoneal lining is the same type of cells as parts of the ovary. This risk is estimated to produce about five cases of peritoneal cancer per 100 women with harmful BRCA1 mutations in the 20 years after the surgery.
BRCA2 related ovarian cancer tends to present in perimenopausal or menopausal women, so salpingo-oophorectomy is recommended between ages 45 and 50. If it is done before menopause, then the women also benefit from a reduced risk of breast cancer.
The surgery is often done in conjunction with a hysterectomy
(surgical removal of the uterus) and sometimes a cervicectomy (surgical removal of the cervix
), especially in women who want to take tamoxifen
, which is known to cause uterine cancer, or who have uterine fibroids. Multiple styles of surgery are available, including larparscopic (keyhole) surgery. Because about 5% of women with a BRCA mutation have undetected ovarian cancer at the time of their planned surgery, the surgery should be treated as if it were a removal of a known cancer.
Salpingo-oophorectomy makes the woman sterile
(unable to bear children). Infertility
services can be used to preserve her eggs
, if wanted. However, as the benefits to the surgery are greatest close to menopause, most women simply postpone the surgery until they have already borne as many children as they choose to.
The surgery also artificially induces menopause, which causes hot flashes, sleep disturbances, mood swings, vaginal dryness, sexual difficulties, difficulty with word recall, and other medical sign
s and symptom
s. The side effects range from mild to severe; most can be treated at least partially. Many women with a BRCA take hormone replacement therapy
to reduce these effects: estrogen-progesterone combinations for women who have a uterus, and unopposed estrogen for women whose uterus was removed. Estrogen can cause breast cancer, but as the amount of estrogen taken is less than the amount produced by the now-removed ovaries, the net risk is usually judged to be acceptable.
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.
s, specifically tamoxifen
, have been found to reduce breast cancer risk in women with BRCA mutations who do not have their breast removed. It is effective as for primary prevention (preventing the first case of breast cancer) in women with BRCA2 mutations, but not BRCA1 mutations, and for secondary prevention (preventing a second, independent breast cancer) in both groups of women. Taking tamoxifen for five years has been found to halve the breast cancer risk in women who have a high risk of breast cancer for any reason, but potentially serious adverse effects like cataract
s, blood clots, and endometrial cancer
, along with quality of life issues like hot flashes, result in some women discontinuing its use and some physicians limiting its use to women with atypical growths in the breasts. Tamoxifen is contraindicated for women who are most likely to be harmed by the common complications. Raloxifene
(Evista), which has a educed risk of side effects, is used as an alternative, but it has not been studied in BRCA mutation carriers specifically. Tamoxifen use can be combined with oophorectomy for even greater reduction of breast cancer risk, particularly in women with BRCA2 mutations.
Aromatase inhibitor
s are medications that prevent estrogen production in the adrenal gland
s 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.
The incidence of ovarian cancer may be reduced by half by taking hormonal contraception
for a total of five or six years. No additional benefit is seen for more than six years' use, and hormonal contraception appears to carry a modest increased risk of causing breast cancer in BRCA mutation carriers. The use of hormonal contraception during teenage years may cause unusually early development of breast cancer in women with BRCA mutations and is discouraged before age 20. The recommendation therefore is for women to take birth control pills for a total of five years in their late 20s or early 30s, as the effect on breast cancer is lowest during these years and highest during middle age.
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. 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.
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. In some studies, only significant, strenuous exercise produced any benefit. Obesity
and weight gain as an adult are associated with breast cancer diagnoses.
Studies on specific foods, diets, or dietary supplement
s have generally produced conflicting information or, in the case of dietary fat, soy consumption, and drinking green tea
, have only been conducted in average-risk women. The only dietary intervention that is generally accepted as preventing breast cancer in BRCA mutation carriers is minimizing consumption of alcoholic beverage
s. Consuming more than one alcoholic drink per day is strongly associated with a higher risk of developing breast cancer, and carriers are usually encouraged to consume no more than one alcoholic drink per day, and no more than four total in a week.
Like the general population, mutation carriers born before 1940 have a much lower risk of being diagnosed with breast cancer by age 50 than those born after 1940. 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.
, pancreatic cancer
, prostate cancer, and colon cancer. Carriers have the normal risks of developing cancer (and other diseases) associated with increased age, smoking, alcohol consumption, poor diet, lack of exercise, and other known risk factors, plus the additional risk from the genetic mutations and an increased susceptibility to damage from ionizing radiation, including natural background radiation
.
Men with BRCA mutations cannot get ovarian cancer, but they may be twice as likely as non-carriers to develop prostate cancer
at a younger age. The risk is smaller and disputed for BRCA1 carriers; up to one-third of BRCA2 mutation carriers are expected to develop prostate cancer before age 65. Prostate cancer in BRCA mutation carriers tends to appear a decade earlier than normal, and it tends to be more aggressive than normal. As a result, annual prostate screening, including a digital rectal examination, is appropriate at age 40 among known carriers, rather than age 50.
Cancer of the pancreas
tends to run in families, even among BRCA families. A BRCA1 mutation approximately doubles or triples the lifetime risk of developing pancreatic cancer; a BRCA2 mutation triples to quintuples it. Between 4% and 7% of people with pancreatic cancer have a BRCA mutation. However, since pancreatic cancer is relatively rare, people with a BRCA2 mutation probably face an absolute risk of about 5%. Like ovarian cancer, it tends not to produce symptoms in the early, treatable stages. Like prostate cancer, pancreatic cancer associated with a BRCA mutation tends to appear about a decade earlier than non-hereditary cases. Asymptomatic screening is invasive and may be recommended only to BRCA2 carriers who also have a family history of pancreatic cancer.
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
.
Cancer of the colon
is approximately as common in both men and women in the developed world as breast cancer is among average-risk women, with about 6% of people being diagnosed with it, usually over the age of 50. Like sporadic prostate cancer, it is a multifactorial disease, and is affected by age, diet, and similar factors. BRCA mutation carriers have a higher than average risk of this common cancer, but the risk is not as high as in some other hereditary cancer syndromes. The risk might be as high as four times normal in some BRCA1 families, and double the normal risk among BRCA2 carriers. Like pancreatic cancer, it may be that only some BRCA mutations or some BRCA families have the extra risk; unlike other BRCA-caused cancers, it does not appear at an earlier age than usual. Normal colon cancer screening is usually recommended to BRCA mutation carriers.
Mutations in BRCA1 and BRCA2 are strongly implicated in some hematological malignancies. BRCA1 mutations are associated acute myelogenous leukemia and chronic myelogenous leukemia
. Mutations of BRCA2 are also found in many T-cell lymphoma
s and chronic lymphocytic leukemia
s.
There is likely little or no effect of a BRCA gene mutation on overall fertility
, although women with a BRCA mutation may be more likely to have primary ovarian insufficiency. BRCA mutation carriers may be more likely to give birth to girls than boys.
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
.
Each pregnancy in genetically typical women is associated with a significantly reduction in the mother's risk of developing breast cancer after age 40. The younger the woman is at the time of her first birth, the more protection against breast cancer she receives. Breastfeeding for more than one year protects against breast cancer. Pregnancy also protects against ovarian cancer in genetically typical women.
Although some studies have produced different results, women with BRCA mutations are generally not expected to receive these significant protective benefits. Current research is too limited and imprecise to permit calculation of specific risks. However, the following general trends have been identified:
and asserts that a defect in the BRCA1 gene might unleash neural growth.
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
and BRCA2
BRCA2
BRCA2 is a protein that in humans is encoded by the BRCA2 gene.BRCA2 orthologs have been identified in most mammals for which complete genome data are available....
. Harmful mutations in these genes produce a hereditary breast-ovarian cancer syndrome in affected families. Mutations in BRCA1 and BRCA2 are uncommon, and breast cancer is relatively common, so these mutations consequently account for only five to ten percent of all breast cancer cases in women.
Hundreds of different types of mutations in these genes have been identified. High-risk mutations, which disable an important error-free DNA repair process, significantly increase the person's risk of developing breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
and other cancers. 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.
Women with harmful mutations in either BRCA1 or BRCA2 have 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. BRCA1 mutations typically confer a higher risk of breast and ovarian cancer in women than BRCA2 mutations. Having a high-risk mutation does not guarantee that the woman will develop any type of cancer, or guarantee that any cancer that appears was actually caused by the mutation, rather than some other factor, like alcohol consumption
Alcohol and cancer
Alcohol is associated with an increased risk of a number of cancers. 3.6% of all cancer cases and 3.5% of cancer deaths worldwide are attributable to consumption of alcohol. Breast cancer in women is linked with alcohol intake...
.
Mutations can be inherited from either parent and may be passed on to both sons and daughters. Each child of a genetic carrier
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
, regardless of sex, has a 50% chance of inheriting the mutated gene from the parent who carries the mutation. As a result, half of the people with BRCA gene mutations are male. The risk of BRCA-related breast cancers for men with the mutation is higher than for other men, but still low. However, BRCA mutations can increase the risk of other cancers, such as colon cancer, pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
, and prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
.
Genes and mutations
Both BRCA genes are tumor suppressor geneTumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
s that produce proteins that are used by the cell in an enzymatic pathway that makes very precise, perfectly matched repairs to DNA molecules that have double-stranded breaks. The pathway requires proteins produced by several other genes, including CHEK2
CHEK2
CHEK2 is the official symbol for the human gene CHK2 checkpoint homolog. It is located on the long arm of chromosome 22.-Function:The protein encoded by this gene, CHK2 a protein kinase that is activated in response to DNA damage and is involved in cell cycle arrest.In response to DNA damage and...
, FANCD2
FANCD2
Fanconi anemia group D2 protein is a protein that in humans is encoded by the FANCD2 gene. The Fanconi anemia complementation group currently includes FANCA, FANCB, FANCC, FANCD1 , FANCD2 , FANCE, FANCF, FANCG, and FANCL.- Function :Fanconi anemia is a genetically heterogeneous recessive disorder...
and ATM. Harmful mutations in any of these genes disable the gene or the protein that it produces.
The cancer risk caused by BRCA1 and BRCA2 mutations are inherited in a dominant fashion. A mutated BRCA gene can be inherited from either parent. Because they are inherited from the parents, they are classified as hereditary or germline mutation
Germline mutation
A germline mutation is any detectable and heritable variation in the lineage of germ cells. Mutations in these cells are transmitted to offspring, while, on the other hand, those in somatic cells are not. A germline mutation gives rise to a constitutional mutation in the offspring, that is, a...
s rather than acquired or somatic mutations. Cancer caused by a mutated gene is a hereditary cancer rather than a sporadic cancer.
Because humans have a diploid genome, each cell has two copies of the gene (one from each biological parent). Typically only one copy contains a disabling, inherited mutation, so the affected person is heterozygous for the mutation. If the functional copy is harmed, however, then the cell is forced to use alternate DNA repair mechanisms, which are more error-prone. The loss of the functional copy is called loss of heterozygosity
Loss of heterozygosity
Loss of heterozygosity in a cell is the loss of normal function of one allele of a gene in which the other allele was already inactivated. This term is mostly used in the context of oncogenesis; after an inactivating mutation in one allele of a tumor suppressor gene occurs in the parent's germline...
(LOH). Any resulting errors in DNA repair may result in cell death or a cancerous transformation of the cell.
There are many variations in BRCA genes, and not all changes confer the same risks. Some variants are harmless; others are known to be very harmful. Some single nucleotide polymorphism
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
s may confer only a small risk, or may only confer risk in the presence of other mutations or under certain circumstances. In other cases, whether the variant is harmful is unknown. Variants are classified as follows:
- Deleterious mutation: The change is proven to cause significant risks. Often, these are frameshift mutationFrameshift mutationA frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...
s 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 unknown significance (VUS): Whether the change has any effect is unknown. 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
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
, 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.
Getting tested
Genetic counselingGenetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
is commonly recommended to people whose personal or family health history suggests a greater than average likelihood of a mutation. Genetic counselors are allied health professionals who are trained to explain genetics to people; some of them are also licensed as registered nurse
Registered nurse
A registered nurse is a nurse who has graduated from a nursing program at a university or college and has passed a national licensing exam. A registered nurse helps individuals, families, and groups to achieve health and prevent disease...
s or social workers. A medical geneticist is a physician who specializes in genetics. 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
Informed consent
Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...
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.
If the client chooses to be tested, then two types of tests are available. Both commonly use a blood sample
Blood Sample
Blood Sample is the 10th studio album by the Finnish avant-garde progressive metal band Waltari.-Track listing:# "Helsinki" - 5:53# "Not Enough" - 3:35# "Too Much Emptiness" - 2:30# "Never" - 4:01# "New York" - 3:48# "I'm in Pain" - 4:38...
, although testing can be done on saliva. The quickest, simplest, and lowest cost test uses positive test results from a blood relative and checks only for the single mutation that is known to be present in the family. If no relative has previously disclosed positive test results, then a full test that checks the entire sequence of both BRCA1 and BRCA2 can be performed. In some cases, ethnicity can be used to narrow the testing to quickly check for common founder mutation
Founder mutation
In genetics, a founder mutation is a mutation that appears in the DNA of one or more individuals who are founders of a distinct population. Founder mutations initiate with changes that occur in the DNA and can get passed down to other generations....
s. For example those with Jewish descent may be tested for the three most common mutations seen among Ashkenazi Jews
Medical genetics of Jewish people
The medical genetics of Jewish people is the study, screening and treatment of genetic disorders that are more common in particular Jewish populations than in the population as a whole. The genetics of Ashkenazi Jews have been particularly well-studied, resulting in the discovery of many genetic...
.
Testing is commonly covered by health insurance
Health insurance
Health insurance is insurance against the risk of incurring medical expenses among individuals. By estimating the overall risk of health care expenses among a targeted group, an insurer can develop a routine finance structure, such as a monthly premium or payroll tax, to ensure that money is...
and public healthcare programs for people at high risk for having a mutation, and not covered for people at low risk. 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 USA 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 oncologist, and the results are always returned to the physician, rather than directly to the patient. How quickly results are returned depends on the test—single-site analysis requires less lab time—and on the infrastructure in place. In the USA, test results are commonly returned within one to several weeks; in Canada, patients commonly wait for eight to ten months for test results.
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.
Testing young children is considered medically unethical
Medical ethics
Medical ethics is a system of moral principles that apply values and judgments to the practice of medicine. As a scholarly discipline, medical ethics encompasses its practical application in clinical settings as well as work on its history, philosophy, theology, and sociology.-History:Historically,...
because the test results would not change the way the child's health is cared for. Because taking birth control pills before age 20 is associated with very early development of breast cancer in BRCA mutation carriers, teenage girls may need to be tested before deciding to take hormonal contraceptives for any reason.
Breast and ovarian cancer risk
Women with deleterious mutations in either the BRCA1 or BRCA2 genes have a high risk of developing breastBreast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and/or ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
. 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.
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.
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
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
treatment or have an oopherectomy. The woman's ten-year risk for ovarian cancer is also increased by 6-12% under these conditions.
Statistics for BRCA-related ovarian cancer typically encompass not only cancer of the ovaries themselves, but also peritoneal cancer and the very rare, but somewhat easier to detect, cancer of the Fallopian tube
Fallopian tube
The Fallopian tubes, also known as oviducts, uterine tubes, and salpinges are two very fine tubes lined with ciliated epithelia, leading from the ovaries of female mammals into the uterus, via the utero-tubal junction...
s. Women with a BRCA mutation have more than 100 times the normal rate of Fallopian tube cancer. These three types of these cancers can be difficult to distinguish in their advanced stages.
When cancer appears
BRCA-related breast cancer appears at an earlier age than average. 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.- BRCA1 is associated with triple-negative breast cancer, which does not respond the hormones and cannot be usefully treated with some drugs, such as Herceptin. Breast cancer often appears about two decades earlier than normal.
- BRCA2 is associated primarily with post-menopausal breast cancer, although the risk of pre-menopausal breast cancer is significant. Like most non-hereditary breast cancers, it is typically responsive to hormones.
BRCA-related ovarian and Fallopian tube cancer is more treatable than average because it is unusually susceptible to platinum-based chemotherapy like cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
. BRCA1-related ovarian cancer appears at younger ages, but the risk for women with BRCA2 climbs markedly at or shortly after menopause.
Survival impact
{| class="infobox" style="width: 14em;"|+ Among women who die before age 70...
|- align="center"
| A 25-year-old woman with no mutation in her BRCA genes has an 84% probability to reach at least the age of 70. 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
Breast cancer screening
Breast cancer screening refers to the medical screening of asymptomatic, apparently healthy women for breast cancer in an attempt to achieve an earlier diagnosis. The assumption is that early detection will improve outcomes...
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.
Women with high-risk BRCA2 mutations, with screening but with no prophylactic medical or surgical intervention, would have only 75% chance to reach age 70, nine percentage points lower than normal. Of those not surviving, 21% would die of breast cancer, 25% ovarian cancer and 54% other causes.
The likelihood of surviving to at least age 70 can be improved by several medical interventions, notably prophylactic mastectomy and oophorectomy.
Male breast cancer
Men with a BRCA mutation have a dramatically elevated relative riskRelative risk
In statistics and mathematical epidemiology, relative risk is the risk of an event relative to exposure. Relative risk is a ratio of the probability of the event occurring in the exposed group versus a non-exposed group....
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. 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.
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
Rice
Rice is the seed of the monocot plants Oryza sativa or Oryza glaberrima . As a cereal grain, it is the most important staple food for a large part of the world's human population, especially in East Asia, Southeast Asia, South Asia, the Middle East, and the West Indies...
, until it has reached a late stage.
Unlike other men, men with a BRCA mutation, especially a BRCA2 mutation, may benefit from professional and self breast exams. Medical imaging is not usually recommended, but because male BRCA2 carriers have a risk of breast cancer that is very similar to the general female population, the standard annual mammogram program can be adapted to these high-risk men.
Screening
An intensive cancer screeningCancer screening
Cancer screening aims to detect cancer before symptoms appear. This may involve blood tests, urine tests, other tests, or medical imaging. The benefits of screening in terms of cancer prevention, early detection and subsequent treatment must be weighed against any harms.Universal screening, mass...
regimen is usually advised for women with deleterious or suspected deleterious BRCA mutations. A typical recommendation includes frequent breast cancer screening
Breast cancer screening
Breast cancer screening refers to the medical screening of asymptomatic, apparently healthy women for breast cancer in an attempt to achieve an earlier diagnosis. The assumption is that early detection will improve outcomes...
as well as tests to detect ovarian cancer.
Breast imaging studies usually include a mammogram once a year, beginning between ages 20 and 30, depending on the age at which any relatives were diagnosed with breast cancer. Breast MRI
Breast MRI
One alternative to mammography, Breast MRI or contrast enhanced magnetic resonance imaging , has shown substantial progress in the detection of breast cancer.-Operation:...
s (magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
) are typically also performed once per year, six months after the mammogram. Breast MRIs use a contrast medium
Contrast medium
A medical contrast medium is a substance used to enhance the contrast of structures or fluids within the body in medical imaging...
to enhance the image, and are far more expensive than mammograms. Mammograms, which are X-ray
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...
s of the breast, expose the patient to some ionizing radiation
Ionizing radiation
Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...
, and BRCA mutations make the person somewhat more likely to develop radiation-induced cancers, so they may be used less frequently in younger carriers. However, the risk-benefit analysis
Risk-benefit analysis
Risk–benefit analysis is the comparison of the risk of a situation to its related benefits. Exposure to personal risk is recognized as a normal aspect of everyday life. We accept a certain level of risk in our lives as necessary to achieve certain benefits. In most of these risks we feel as though...
shows that annual mammograms are appropriate. Both tests are commonly conducted because they each have strengths and weaknesses. Mammograms are better at identifying calcium microdeposits that are characteristic of some precancerous tissue changes. MRIs show more details in women with dense breast tissue, but the false positive rate (the tissue is actually healthy, but MRI suggests that cancer may be present) can be as high as 50%. Additionally, clinical breast exams and breast self-exams, which do not save lives in the general, asymptomatic population, are appropriate for women with BRCA mutations.
Alternatives include breast ultrasonography, CT scans, PET scans, scintimammography
Scintimammography
Scintimammography is a type of breast imaging test that is used to detect cancer cells in the breasts of some women who have had abnormal mammograms, or who have dense breast tissue, but is not used for screening or in place of a mammogram...
, elastography
Elastography
Elastography is a non-invasive method in which stiffness or strain images of soft tissue are used to detect or classify tumors. A tumor or a suspicious cancerous growth is normally 5-28 times stiffer than the background of normal soft tissue. When a mechanical compression or vibration is applied,...
, thermography, ductal lavage
Ductal lavage
Ductal lavage is a method used to collect cells from milk ducts in the breast. A hair-size catheter is inserted into the nipple, and a small amount of salt water is released into the duct. The water picks up breast cells, and is removed. The cells are checked under a microscope...
, 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
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
for CA-125
CA-125
CA-125 also known as mucin 16 or MUC16 is a protein that in humans is encoded by the MUC16 gene. MUC16 is a member of the mucin family glycoproteins...
and clinical pelvic exams. The blood test has relatively poor sensitivity and specificity
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
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.
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.
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.- Tubal ligationTubal ligationTubal ligation or tubectomy is a surgical procedure for sterilization in which a woman's fallopian tubes are clamped and blocked, or severed and sealed, either method of which prevents eggs from reaching the uterus for fertilization...
is the least invasive of these surgeries and and appears to reduce ovarian cancer risk for BRCA1BRCA1BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
carriers (but not BRCA2BRCA2BRCA2 is a protein that in humans is encoded by the BRCA2 gene.BRCA2 orthologs have been identified in most mammals for which complete genome data are available....
carriers) by over 60%. It can be performed anytime after childbearing is complete and may be reversible. Unlike other surgeries, it does not reduce the risk of breast cancer. - Prophylactic (preventive) mastectomyMastectomyMastectomy is the medical term for the surgical removal of one or both breasts, partially or completely. Mastectomy is usually done to treat breast cancer; in some cases, women and some men believed to be at high risk of breast cancer have the operation prophylactically, that is, to prevent cancer...
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 drop ovarian cancer risk, and a large drop 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.
- HysterectomyHysterectomyA hysterectomy is the surgical removal of the uterus, usually performed by a gynecologist. Hysterectomy may be total or partial...
has no direct effect on BRCA-related cancers, but it enables the women to use some medications that reduce breast cancer risk (such as tamoxifenTamoxifenTamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
) with the risk of uterine cancerUterine cancerThe term uterine cancer may refer to any of several different types of cancer which occur in the uterus, namely:*Uterine sarcomas: sarcomas of the myometrium, or muscular layer of the uterus, are most commonly leiomyosarcomas.*Endometrial 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.
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.
- 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.
Prophylactic 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.Bilateral mastectomy is the removal of both breasts by a breast surgeon. The modified radical mastectomy is only used in women diagnosed with invasive breast cancer. Techniques for prophylactic mastectomies include:
- 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 foldInframammary foldInframammary fold , inframammary crease or inframammary line is the feature of human anatomy which is a natural boundary of a breast from below, the place where the breast and the chest meet. The choice of the term depends on the prominence of the feature. It is also sometimes called inframammary...
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.
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 breast reconstruction surgery for aesthetic purposes. Women who choose a flat-chested appearance or use external breast prostheses typically choose simple mastectomy, with its greater risk reduction.
Breast reconstruction is usually done by a plastic surgeon, and may be started as part of the same multi-hour surgery that removes the breasts. Multiple techniques for reconstruction have been used, with different locations and amounts of scarring. Some techniques use tissue from another part of the body, such as fat tissue from the lower abdomen or occasionally muscles from other parts of the torso. Others use breast implants, possibly preceded by tissue expanders, to provide volume. Some reconstruction techniques require multiple surgeries. Afterwards, some women have tattoo
Tattoo
A tattoo is made by inserting indelible ink into the dermis layer of the skin to change the pigment. Tattoos on humans are a type of body modification, and tattoos on other animals are most commonly used for identification purposes...
s added to simulate breast areolas or have the skin reshaped to form a nipple.
Prophylactic salpingo-oophorectomy
OophorectomyOophorectomy
Oophorectomy is the surgical removal of an ovary or ovaries. The surgery is also called ovariectomy, but this term has been traditionally used in basic science research describing the surgical removal of ovaries in laboratory animals...
(surgical removal of the ovaries) and salpingectomy
Salpingectomy
Salpingectomy refers to the surgical removal of a Fallopian tube.-Indications:The procedure was first performed by Lawson Tait in patients with a bleeding ectopic pregnancy; this procedure has since saved the lives of countless women...
(surgical removal of the Fallopian tubes) are strongly recommended to women with BRCA mutations. Salpingo-oophorectomy is the single most effective method of preventing ovarian and Fallopian tube cancer in women with a BRCA mutation. However, a small risk of primary peritoneal cancer
Primary peritoneal cancer
Primary peritoneal cancer or carcinoma is also known as: serous surface papillary carcinoma, primary peritoneal carcinoma, extra-ovarian serous carcinoma, primary serous papillary carcinoma, psammomacarcinoma. It was historically classified under "carcinoma of unknown primary"...
remains, at least among women with BRCA1 mutations, since the peritoneal lining is the same type of cells as parts of the ovary. This risk is estimated to produce about five cases of peritoneal cancer per 100 women with harmful BRCA1 mutations in the 20 years after the surgery.
BRCA2 related ovarian cancer tends to present in perimenopausal or menopausal women, so salpingo-oophorectomy is recommended between ages 45 and 50. If it is done before menopause, then the women also benefit from a reduced risk of breast cancer.
The surgery is often done in conjunction with a hysterectomy
Hysterectomy
A hysterectomy is the surgical removal of the uterus, usually performed by a gynecologist. Hysterectomy may be total or partial...
(surgical removal of the uterus) and sometimes a cervicectomy (surgical removal of the cervix
Cervix
The cervix is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall...
), especially in women who want to take tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
, which is known to cause uterine cancer, or who have uterine fibroids. Multiple styles of surgery are available, including larparscopic (keyhole) surgery. Because about 5% of women with a BRCA mutation have undetected ovarian cancer at the time of their planned surgery, the surgery should be treated as if it were a removal of a known cancer.
Salpingo-oophorectomy makes the woman sterile
Sterility (physiology)
Sterility is the physiological inability to effect sexual reproduction in a living thing, members of whose kind have been produced sexually. The term may be used in reference to* types of organism, such as the mule, a sterile hybrid;...
(unable to bear children). Infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
services can be used to preserve her eggs
Ovum
An ovum is a haploid female reproductive cell or gamete. Both animals and embryophytes have ova. The term ovule is used for the young ovum of an animal, as well as the plant structure that carries the female gametophyte and egg cell and develops into a seed after fertilization...
, if wanted. However, as the benefits to the surgery are greatest close to menopause, most women simply postpone the surgery until they have already borne as many children as they choose to.
The surgery also artificially induces menopause, which causes hot flashes, sleep disturbances, mood swings, vaginal dryness, sexual difficulties, difficulty with word recall, and other medical sign
Medical sign
A medical sign is an objective indication of some medical fact or characteristic that may be detected by a physician during a physical examination of a patient....
s and symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s. The side effects range from mild to severe; most can be treated at least partially. Many women with a BRCA take hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
to reduce these effects: estrogen-progesterone combinations for women who have a uterus, and unopposed estrogen for women whose uterus was removed. Estrogen can cause breast cancer, but as the amount of estrogen taken is less than the amount produced by the now-removed ovaries, the net risk is usually judged to be acceptable.
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.
Chemoprevention
Selective estrogen receptor modulatorSelective estrogen receptor modulator
Selective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...
s, specifically tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
, have been found to reduce breast cancer risk in women with BRCA mutations who do not have their breast removed. It is effective as for primary prevention (preventing the first case of breast cancer) in women with BRCA2 mutations, but not BRCA1 mutations, and for secondary prevention (preventing a second, independent breast cancer) in both groups of women. Taking tamoxifen for five years has been found to halve the breast cancer risk in women who have a high risk of breast cancer for any reason, but potentially serious adverse effects like cataract
Cataract
A cataract is a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light...
s, blood clots, and endometrial cancer
Endometrial cancer
Endometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
, along with quality of life issues like hot flashes, result in some women discontinuing its use and some physicians limiting its use to women with atypical growths in the breasts. Tamoxifen is contraindicated for women who are most likely to be harmed by the common complications. Raloxifene
Raloxifene
Raloxifene is an oral selective estrogen receptor modulator that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast...
(Evista), which has a educed risk of side effects, is used as an alternative, but it has not been studied in BRCA mutation carriers specifically. Tamoxifen use can be combined with oophorectomy for even greater reduction of breast cancer risk, particularly in women with BRCA2 mutations.
Aromatase inhibitor
Aromatase inhibitor
Aromatase inhibitors are a class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women. AIs may also be used off-label to treat or prevent gynaecomastia in men....
s are medications that prevent estrogen production in the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
s and adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
. 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.
The incidence of ovarian cancer may be reduced by half by taking hormonal contraception
Hormonal contraception
Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The original hormonal method—the combined oral contraceptive...
for a total of five or six years. No additional benefit is seen for more than six years' use, and hormonal contraception appears to carry a modest increased risk of causing breast cancer in BRCA mutation carriers. The use of hormonal contraception during teenage years may cause unusually early development of breast cancer in women with BRCA mutations and is discouraged before age 20. The recommendation therefore is for women to take birth control pills for a total of five years in their late 20s or early 30s, as the effect on breast cancer is lowest during these years and highest during middle age.
Non-medical choices
Given the high risks and the low benefit of lifestyle choices in BRCA mutation carriers, no lifestyle choices provide sufficient protection.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. 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.
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. In some studies, only significant, strenuous exercise produced any benefit. Obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
and weight gain as an adult are associated with breast cancer diagnoses.
Studies on specific foods, diets, or dietary supplement
Dietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
s have generally produced conflicting information or, in the case of dietary fat, soy consumption, and drinking green tea
Green tea
Green tea is made solely from the leaves of Camellia sinensis that have undergone minimal oxidation during processing. Green tea originates from China and has become associated with many cultures throughout Asia. It has recently become more widespread in the West, where black tea is traditionally...
, have only been conducted in average-risk women. The only dietary intervention that is generally accepted as preventing breast cancer in BRCA mutation carriers is minimizing consumption of alcoholic beverage
Alcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
s. Consuming more than one alcoholic drink per day is strongly associated with a higher risk of developing breast cancer, and carriers are usually encouraged to consume no more than one alcoholic drink per day, and no more than four total in a week.
Like the general population, mutation carriers born before 1940 have a much lower risk of being diagnosed with breast cancer by age 50 than those born after 1940. The reasons for the difference is unknown. Unlike the general population, age at menarche
Menarche
Menarche is the first menstrual cycle, or first menstrual bleeding, in female human beings. From both social and medical perspectives it is often considered the central event of female puberty, as it signals the possibility of fertility....
and age at menopause has no effect on breast cancer risk for BRCA mutation carriers.
Other cancers
Mutations have been associated with increased risk of developing any kind of invasive cancer, including stomach cancerStomach cancer
Gastric cancer, commonly referred to as stomach cancer, can develop in any part of the stomach and may spread throughout the stomach and to other organs; particularly the esophagus, lungs, lymph nodes, and the liver...
, pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
, prostate cancer, and colon cancer. Carriers have the normal risks of developing cancer (and other diseases) associated with increased age, smoking, alcohol consumption, poor diet, lack of exercise, and other known risk factors, plus the additional risk from the genetic mutations and an increased susceptibility to damage from ionizing radiation, including natural background radiation
Background radiation
Background radiation is the ionizing radiation constantly present in the natural environment of the Earth, which is emitted by natural and artificial sources.-Overview:Both Natural and human-made background radiation varies by location....
.
Men with BRCA mutations cannot get ovarian cancer, but they may be twice as likely as non-carriers to develop prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
at a younger age. The risk is smaller and disputed for BRCA1 carriers; up to one-third of BRCA2 mutation carriers are expected to develop prostate cancer before age 65. Prostate cancer in BRCA mutation carriers tends to appear a decade earlier than normal, and it tends to be more aggressive than normal. As a result, annual prostate screening, including a digital rectal examination, is appropriate at age 40 among known carriers, rather than age 50.
Cancer of the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
tends to run in families, even among BRCA families. A BRCA1 mutation approximately doubles or triples the lifetime risk of developing pancreatic cancer; a BRCA2 mutation triples to quintuples it. Between 4% and 7% of people with pancreatic cancer have a BRCA mutation. However, since pancreatic cancer is relatively rare, people with a BRCA2 mutation probably face an absolute risk of about 5%. Like ovarian cancer, it tends not to produce symptoms in the early, treatable stages. Like prostate cancer, pancreatic cancer associated with a BRCA mutation tends to appear about a decade earlier than non-hereditary cases. Asymptomatic screening is invasive and may be recommended only to BRCA2 carriers who also have a family history of pancreatic cancer.
Melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
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
Melanocytic nevus
A melanocytic nevus is a type of lesion that contains nevus cells .Some sources equate the term mole with "melanocytic nevus". Other sources reserve the term "mole" for other purposes....
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
Uveal melanoma
Uveal melanoma is a cancer of the eye involving the iris, ciliary body, or choroid . Tumors arise from the pigment cells that reside within the uvea giving color to the eye...
.
Cancer of the colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
is approximately as common in both men and women in the developed world as breast cancer is among average-risk women, with about 6% of people being diagnosed with it, usually over the age of 50. Like sporadic prostate cancer, it is a multifactorial disease, and is affected by age, diet, and similar factors. BRCA mutation carriers have a higher than average risk of this common cancer, but the risk is not as high as in some other hereditary cancer syndromes. The risk might be as high as four times normal in some BRCA1 families, and double the normal risk among BRCA2 carriers. Like pancreatic cancer, it may be that only some BRCA mutations or some BRCA families have the extra risk; unlike other BRCA-caused cancers, it does not appear at an earlier age than usual. Normal colon cancer screening is usually recommended to BRCA mutation carriers.
Mutations in BRCA1 and BRCA2 are strongly implicated in some hematological malignancies. BRCA1 mutations are associated acute myelogenous leukemia and chronic myelogenous leukemia
Chronic myelogenous leukemia
Chronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood...
. Mutations of BRCA2 are also found in many T-cell lymphoma
T-cell lymphoma
The T-cell lymphomas are the four types of lymphoma that affect T cells. These account for perhaps one in ten cases of non-Hodgkin lymphoma.They can be associated with Epstein Barr virus and Human T-cell leukemia virus-1.-Types:The four classes are:...
s and chronic lymphocytic leukemia
Chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...
s.
Childbearing and fertility effects
Whether to have children is a significant source of stress for women who learn of their BRCA mutations during their childbearing years.There is likely little or no effect of a BRCA gene mutation on overall fertility
Fertility
Fertility is the natural capability of producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...
, although women with a BRCA mutation may be more likely to have primary ovarian insufficiency. BRCA mutation carriers may be more likely to give birth to girls than boys.
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
Fanconi anemia
Fanconi anemia is a genetic disease with an incidence of 1 per 350,000 births, with a higher frequency in Ashkenazi Jews and Afrikaners in South Africa.FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair...
.
Each pregnancy in genetically typical women is associated with a significantly reduction in the mother's risk of developing breast cancer after age 40. The younger the woman is at the time of her first birth, the more protection against breast cancer she receives. Breastfeeding for more than one year protects against breast cancer. Pregnancy also protects against ovarian cancer in genetically typical women.
Although some studies have produced different results, women with BRCA mutations are generally not expected to receive these significant protective benefits. Current research is too limited and imprecise to permit calculation of specific risks. 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. 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. Similar to genetically typical women, breastfeeding for more than one year significantly protects against breast cancer, and pregnancy protects against ovarian cancer in BRCA1 women. The effect, if any, of long-term breastfeeding on ovarian cancer is unclear.
- For women with a BRCA2 mutation, each pregnancy is paradoxically associated with a statistically significant increase in the risk for breast cancer. Unlike genetically typical women or women with BRCA1 mutations, breastfeeding has no effect on either cancer in women with BRCA2 mutations. Limited and conflicting data suggests that, also unlike other women, pregnancy may not reduce ovarian cancer risk significantly in women with a BRCA2 mutation; in fact, one study suggested that pregnancy might increase their risk of ovarian cancer.
Evolutionary advantage of BRCA mutations
Several theories assert that BRCA mutations have evolutionary advantages, such as higher intelligence. The Ashkenazi intelligence theory was proposed by Gregory CochranGregory Cochran
Gregory M. Cochran is a physicist and adjunct professor of anthropology at the University of Utah who has developed some new ideas in evolutionary medicine and genetic anthropology. Cochran is known for several controversial theories....
and asserts that a defect in the BRCA1 gene might unleash neural growth.
External links
- BOADICEA, a risk estimator tool for familial breast and ovarian cancer
- Table showing likelihood of survival, depending on screening and prevention choices made by women with a BRCA mutation