Brca1 & Brca2 Are Women More Susceptible to Breast and Ovarian Cancer If a Mutation in BRCA1 and BRCA2 is Found Breast and Ovarian cancer are the two most common kinds of cancers found in women in the United States. An estimated 90-95% of cancer cases are believed to be environmental and lifestyle related. The remaining five to ten percent of these types of cancers may be caused by inherited genetic mutations. The existence of a breast cancer susceptibility gene known as BRCA1 and its approximate location on human chromosome 17 have been known for about 4 years, on the basis of retrospective family studies. But only since 1994 have scientist actually been able to isolate and sequence the gene.
In 1995, BRCA2 (a similar gene) was identified. In some families, the gene is inherited in a mutated form. Women who inherit a mutated form are highly susceptible to breast and ovarian cancers. BRCA1 and BRCA2 are two known genes that are responsible for an increased risk of both breast and ovarian cancer. (Malone 136) What is cancer? Cancer is defined as a disease in which abnormal cells multiply without control, destroying healthy tissue and endangering life. Cancer occurs in most species of animals and in many kinds of plants, as well as human beings. About 100 types of cancers attack human beings. BRCA1 and BRCA2 are genes linked to breast (male and female), prostate, ovarian, and colon cancer. (Harris 1) Cancer strikes people of all ages, but especially middle-aged to elderly people.
It occurs equally among both males and females. The disease can attack any part of the body and may spread through means of blood flow. Cancer may spread only if it is not caught in time. Many types of cancers are determined in various stages in which they can be treated and possibly cured. (Harris 2) The occurrence of a specific kind of cancer varies from country to country. For example cancer of the stomach is much more common in Japan than in the United States.
The primary body sites that cancer strikes most often are the skin; the female breasts; and the organs of the digestive, respiratory, reproductive, blood-forming, lymphatic, and urinary systems. (Harris 2) The body of an adult human being is made up of hundreds of billions of cells. Each minute, several billion of these die and are replaced several billion new cells. Each if these new cells then doubles in size and becomes capable of dicing throughout mitosis. This way, new cells are being produced for every cell that dies.
Normal, non-cancerous cells, divide at a normal rate required to replace dying cells, never at a faster rate. Like normal cells, cancer cells reproduce by dividing, but have lost the ability to reproduce at a controlled rate. (Collins 183) Whenever anything interferes with the reproductive control of cells, the cells multiply and gradually build up a mass of tissue called a tumor. Tumors that are benign do not spread, while tumors that are malignant do spread and destroy other parts of the body. The spread of cancer from one part of the body to the other is known as metastasis.
Cancers ability to spread makes the disease extremely difficult to treat unless detected early. (Harris 4) Most experts agree that people develop cancer mainly through prolonged contact with one or more carcinogens. In addition, scientists suspect that a person may inherit a tendency to develop the disease as well, linking it to DNA alterations. Carcinogens attack normal cells and may eventually cause one of the cells to become cancerous. Scientists believe that 90 to 95% of cancer start this way. The changes are then passed on to the cells descendants. One cancerous cell turns into two, and two into four, and four into eight, and so on.
Carcinogens are introduced into the body through the nose, mouth, or some other bodily openings. Many cancers are caused by a combination of two or more agents usually rather than a single one. (Harris 7) Some cancers, including those of the breast and colon, occur among blood relatives at a higher than average rate. Scientist believe that some people inherit a tendency to develop a certain type of cancer. Only a few types of cancer though have been proven to be hereditary, such as, breast and ovarian cancer.
In addition researchers have identified certain genes, called proto-oncogenes, that are vital to early tissue development. When these genes become changed or rearranged by chemicals or viruses, these genes in their altered state are called oncogenes. The oncogenes than transform a healthy cell into a cancerous cell. Scientists have identified over 50 oncogenes that may cause cancer in certain organs such as the bladder, breasts, liver, lungs, colon, and pancreas. Some scientists believe that oncogenes are involved in all cancers, while others do not.
(Harris 7) Breast cancer is one of the most common types of cancer among American women, affecting 1 in 10 during their life time. It is estimated that 45% of all families with significantly high breast cancer incidence, and at least 80% of families with elevated rates of both early-onset breast cancer and ovarian cancer, carry the mutated BRCA1 gene. A rough estimate is that 1 in 200 women in the U.S may have an inherited mutation in the gene. (American Cancer Society packet) Up until the 1940s many doctors and scientist thought breast cancer was a result of old aging. Scientists know now that breast cancer is not a result of old aging, but a result of being in contact with too many carcinogens, or as a result of inheriting certain genes. It is becoming more and more clear, that all cancers i.e.
breast cancer, have a strong genetic basis, not necessary meaning that they are all hereditary, but can be found linked to certain genes on chromosomes. (Love 165) Normal cells have 46 chromosomes which appear in 23 pair, but cancer cells usually have many more and on occasion fewer. The risks of developing breast cancer comes from either parent. Because each person has two copies of each gene, but transmits only one copy to each of his or her offspring, the laws of chance predict that about half of all children of a parent with a mutation in the BRCA1 gene will inherit the alteration. This flawed gene will make you more susceptible to cancer.
The most common genes in women and men, that when damaged cause breast cancer are BRCA1 and BRCA2. BRCA1 and BRCA2 are also linked to an increased risk for ovarian cancer as well as breast cancer. (Love 167) Usually breast and ovarian cancer are not inherited. It has been estimated that about 5 to 10% of all breast and ovarian cancers are thought to be due to mutations in a gene inherited from a parent. However, if an individual has several closely related family members with breast and/or ovarian cancer, or if cancer has occurred at an early age, there is higher suspicion that the breast cancer in that family may be an inheritance.
(Scalia 1) BRCA1: BR=breast CA=cancer gene 1, located on chromosome 17q, was first discovered in 1994 by Mark Skolnick at Myriad Genetics Corp. BRCA1 normally is responsible for making proteins which is important for the normal functions of the cells. A mutation in BRCA1 can change the protein it makes so the protein does not work as well. The BRCA1 gene is encoded by 5591 nucleotides distributed over a gnomic region which is approximately 100kb in length. (Langston 3) SEE DIAGRAM 1 It is possible that the BRCA1 gene may be involved in some sporadic cases through somatic mutations (mutations that cannot be passed to offspring) that occur in DNA of breast cells during a womans lifetime.
Preliminary evidence, however, suggests that BRCA1 plays a small role, if any, in sporadic breast cancer. (Langston 4) BRCA2: BR=breast CA=cancer gene 2 was discovered in 1995 by Dr. Steven Narod in Ontario, Canada. Twenty-two coding exons of the gene encode a protein of 1863 amino acids. The protein contains a putative RING finger domain near the amino-terminal, suggesting BRCA2 may regulate transcription. (Levine 25) DIAGRAM 1 BRCA2, located on chromosome 13q, functions similar to BRCA1.
The only real difference between BRCA1 and BRCA2 is that BRCA2 increases the risk for male cancer, while BRCA1 does not. Also the estimated risk of ovarian cancer with BRCA2 is not as high as BRCA1. (Langston 3) When researchers isolated these gene, they looked at selected individuals with either breast and/or ovarian cancer. The researchers who isolated the gene looked for BRCA1 mutations in 32 breast tumors and 12 ovarian tumors from patients who were not known to be members of cancer-prone families. From this test scientists found BRCA1 mutations in three of the breast tumors and in one of the ovarian tumors. However, each of the four was found to be a germline mutation, which suggests that these patients have inherited a BRCA1 gene mutation in the same way as women from the families that have been studied.
Future research will clarify if BRCA1 has any role in sporadic breast cancers. Studies of families with inherited alterations in BRCA1 has suggested that more than half the women who carry a cancer associated mutation in the gene will be diagnosed with breast cancer by age 50. (American Can Soc Pack 3) Since the isolation of these genes, studies characterizing the effects of specific mutations are presently being conducted. Existing tests to determine whether a person carries a BRCA1 mutation are effected on both research on commercial levels. Once the gene is identified in a family, researchers can look directly for the specific mutation. This allows testing for family members to be much more easy, as well as less expensive. (Rizzler 24) In women who have been found to carry an altered BRCA1 gene, the risk to develop breast cancer by age 70 may be as high as 80.5% and the risk for ovarian cancer 40 to 60%. In other words, out of a 100 women who inherit BRCA1 mutations, about 80 will develop cancer by the time they reach 70 years; about 40-60 women will develop ovarian cancer.
For women who develop cancer in one of the breasts, the risk is increased for cancer to develop in the other breast as well. Men who carry a mutation in BRCA1 do not seem to have high risk to develop breast cancer, but there may be a slightly increased risk for prostate cancer or colon cancer. (Bre Ova PAMPHLET) We all have two BRCA1 and BRCA2 genes. We get these genes from both our mother and our father. A mutation in either of these genes can be inherited from either parent. If the mother or father does have a mutation then each of his or her children has a 50% chance of inheriting the mutation.
Chance determines who inherits the gene and who does not, and the appearance of the gene in one child has no effect on the risk in other children in the family. It is possible that all or none of the offspring of an affected parent will inherit the mutated gene. (Scalia 1) SEE DIAGRAM 2 BRCA1 and BRCA2 in their natural form, are thought to be important for normal function of cells. Because BRCA1 is a gene that has recently been identified, little is known either of its role in breast cancer development or its normal function. If there is a mutation, however, in either of these genes, or one copy of either gene is lost or damaged, its function may be disrupted, making breast cells and ovarian cells more prone to the susceptibility of developing cancer. Not everyone who inherits a mutation in BRCA1 and BRCA2 develops breast or ovarian cancer.
BRCA1 or BRCA2 mutation does not cause cancer; however it does increase the chances for a person to develop cancer. Scientists do not know why only some individuals with a mutation develop cancer and why some do not, however, with the rapid progression of cancer research and genetic testing these questions may soon be resolved. (Scalia 1) Everyone has two genes of a specific trait. One from mom and one from dad. If one of these genes becomes mutated, or lost, then the other can serve as a break for the other and continue to function as normal.
Women with inherited BRCA1 mutation are born with one bad copy, so that for cancer to occur they need only one additional damaging mutation in a breast cell some time during life. It is suspected that the BRCA1 and BRCA2 genes function as a tumor suppressor. Suppressor genes normally prevent uncontrolled cell proliferation and their inactivation through mutation can lead to cancer. Inherited mutation occurs only on one gene, while the other is not effected. Chances of that person developing cancer from one of these genes is greatly increased, i.e. 85% breast cancer and 50% for ovarian cancer.
(Scalia) SEE DIAGRAM 3 & 4 One study published in the March 19, 1994 issue of the Lancet suggested that more than 40% of women with a mutated BRCA1 gene may develop ovarian cancer. Also in this study, both male and female carriers of BRCA1 mutations had significantly elevated risks of colon cancer, and male carriers had increased risk of prostate cancer. (American Cancer Society) Only about half (45%) of all inherited breast cancers is due to mutations in BRCA1. About 35% is due to mutations in BRCA2. There may be other genes which increase the risks for developing breast cancer as well. Scientists speculate there might even be a BRCA3 and a BRCA4 gene. Right now scientists do know of two other genes, tP53 and ATM, that might cause a person to develop breast cancer; tP53 is involved in breast cancer development only when a person has the Li-Fraumency syndrome.
Scientists know little about these genes and do speculate that ATM only effects the breast tissue in combination with certain syndromes. (Cummings pg. 5) By studying normal cells and cancer cells under microscopes, cell biologists have discovered important differences in the cells behavior. They have found that during the process of mitosis, a series of carefully orchestrated steps, normal cells continue dividing until they come in contact with neighboring cells. Cell division then stops.
This characteristic of normal cells is called contact inhibition. Cells that develop cancer have lost contact inhibition. They continue to divide even after they have come into contact with other cells. (Kormanicky 56) BRCA1 and mRNA levels were found invariably low in tumors from BRCA1 mutations carriers. As a tumor grows it needs nourishment.
The tumor sends out protein messengers called tumor aniogene factors to get the material it needs. Normal breast epithelium surrounding the BRCA1 tumors showed higher mRNA levels than tumor tissue, indicating that the low mRNA levels were due to somatic inactivation of the wild-type BRCA1 gene. (Komanicky 56) Cell biologists have developed methods of destroying cancer cells without damaging healthy cells. They are also trying to learn how cancer-causing oncogenes are activated and how they can be turned off. If scientists learn how to deactivate oncogenes, they may find ways of controlling the reproduction of a cancer cells.
Such type of genes that may be able to turn off are BRCA1 and BRCA2. The process on how one would turn these genes off is still not devised yet. (Myriad Genetics Pat …