BRCA mutation

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 examine 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. 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. The woman's ten-year risk for ovarian cancer is also increased by 6-12% under these conditions. • 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. BRCA1-related ovarian cancer appears at younger ages, but the risk for women with BRCA2 climbs markedly at or shortly after menopause. 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. Childbearing 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. 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, however this observation has been attributed to ascertainment bias. If both parents are carriers of a BRCA mutation, then pre-implantation genetic diagnosis is sometimes used to prevent the birth of a child with BRCA mutations. The effect, if any, of long-term breastfeeding on ovarian cancer is unclear. For live cases, inheriting both mutations leads to a grave prognosis, characterized by Wilms tumors, leukemias, and early-onset brain malignancies. ==Genetics==

fashion, from either parent. Both BRCA genes are tumor suppressor genes that produce proteins that are used by the cell in an enzymatic pathway that make very precise, perfectly matched repairs to DNA molecules that have double-stranded breaks. The pathway requires proteins produced by several other genes, including CHK2, FANCD2 and ATM. This is because people with the mutation are likely to acquire a second mutation, leading to dominant expression of the cancer. A mutated BRCA gene can be inherited from either parent. Because they are inherited from the parents, they are classified as hereditary or germline mutations rather than acquired or somatic mutations. Cancer caused by a mutated gene inherited from an individual's parents 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. Some variants are harmless; others are known to be very harmful. Some single nucleotide polymorphisms 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 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 reclassified. • 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. 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. • 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 • Women affected by triple negative breast cancer (TNBC) (estrogen receptor negative, progesterone receptor negative, and HER2/neu negative) under the age of 50 • Two relatives (FDR/SDR) diagnosed under the age of 45 • Three relatives (FDR/SDR) diagnosed with an average age of 50 or less • Four relatives of any age • 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 Testing young children is considered medically unethical because the test results would not change the way the child's health is cared for. Parents with BRCA mutations often struggle with sharing their inherent risk of developing cancer at some point in their lifetime. Many fear that their child will experience increased fear and anxiety regarding their parents’s health and their own health. Tailoring this conversation to the child’s age and maturity level, while also keeping the goals of this conversation in mind may make it more meaningful and effective, rather than inducing fear or worry. Genetic counseling professionals can help by advising when children should be tested or begin preventative measures, distinguishing between relevant and irrelevant information to share with others, providing psychological and educational resources, communicating information to at-risk individuals, or explaining results to individuals in an accessible manner. Test procedure 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, because of the founder effect, Jewish ethnicity can be used to narrow the testing to quickly check 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 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 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 US, test results are commonly returned within one to several weeks; in Canada, patients commonly wait for eight to ten months for test results. Test interpretation 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. == Psychological implications of BRCA genetic testing ==

The increased risk of developing different types of cancer due to a positive BRCA result can be very psychologically distressing for some individuals. Genetic counseling is often required before and after undergoing testing, regardless of the result, but often does not follow patients longitudinally. As genetic testing becomes more common place, more genetic counseling resources may be necessary in order to reduce the psychological distress that occurs in individuals. Some types of psychosocial resources used in genetic counseling include educational pamphlets and modules using medically-accessible language, decision-making aids, visual educational aids, or home-based counseling. Anxiety is one of the most common psychosocial proponents towards genetic testing, with many patients reporting fear of developing cancer. Even after negative results for the BRCA mutation, many individuals still struggle with the same level pre-test anxiety. Following genetic testing, individuals with results showing that they are carriers experienced increased psychological distress, especially compared to their non-carrier counterparts. Genetic counseling has been found to reduce cancer-specific anxiety and depression while also increasing understanding of risk. ==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. 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. 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). 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. Medication Birth control pills are associated with substantially lower risk of ovarian cancer in women with BRCA mutations. A 2013 meta-analysis found that oral contraceptive use was associated with a 42% reduction of the relative risk of ovarian cancer, the association was similar for BRCA1 and BRCA2 mutations. Use of oral contraceptives was not significantly associated with breast cancer risk, although a small increase in risk that did not reach statistical significance was observed. Selective estrogen receptor modulators, specifically tamoxifen, have been found to reduce breast cancer risk in women with BRCA mutations who do not have their breasts removed. 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. • 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. • 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 substantial 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 develop them. People also have different values. They may choose to focus on total cancer prevention, psychological benefits, current quality of life, or overall survival. The potential impact of future medical developments in treatment or prognosis may be important for very young women and family planning. The decision is individualized and is usually based on many factors, such as the earliest occurrence of BRCA-related cancer in close relatives. An increasing number of 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. The protective effect of prophylactic surgery is greater when done at a 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 offers little or no additional survival advantage, but it does increase the adverse effects of 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 surviving 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. Due to limited evidence, a 2019 meta-analysis was unable to conclude 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. (See #Childbearing for a discussion on ovarian cancer rates.) Being physically active and maintaining a healthy body weight reduces the risk of breast and other cancers in the general population and lowers the risk of 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 does not affect 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 supplements 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 beverages. Consuming more than one alcoholic drink per day is strongly associated with a higher risk of developing breast cancer. Carriers are usually encouraged to consume no more than one alcoholic drink per day, and no more than four total in a week. 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. The reasons for the difference are unknown. Unlike the general population, age at menarche and age at menopause do not affect breast cancer risk for BRCA mutation carriers. ==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. ==Patents==

A patent application for the isolated BRCA1 gene and cancer-cancer promoting mutations discussed above, as well as methods to diagnose the likelihood of getting breast cancer, was filed by the University of Utah, National Institute of Environmental Health Sciences (NIEHS) and Myriad Genetics in 1994; The patents began to expire in 2014. 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." Peter Meldrum, CEO of Myriad Genetics, has acknowledged that Myriad has "other competitive advantages that may make such [patent] enforcement unnecessary" in Europe. == See also ==