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    Brca1 & Brca2 Essay (4468 words)

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    Are Women MoreSusceptibleto Breast and OvarianCancer If a Mutation inBRCA1 and BRCA2 isFoundBreast and Ovarian cancer are the two most common kinds of cancers found in women in the United States. An estimated 90-95% of cancer casesare believed to be environmental and lifestyle related.

    The remaining five toten percent of these types of cancers may be caused by inherited geneticmutations. The existence of a breast cancer susceptibility gene known asBRCA1 and its approximate location on human chromosome 17 have beenknown for about 4 years, on the basis of retrospective family studies. Butonly since 1994 have scientist actually been able to isolate and sequence thegene. In 1995, BRCA2 (a similar gene) was identified. In some families, thegene is inherited in a mutated form. Women who inherit a mutated form arehighly susceptible to breast and ovarian cancers.

    BRCA1 and BRCA2 aretwo known genes that are responsible for an increased risk of both breast andovarian cancer. (Malone 136)What is cancer? Cancer is defined as a disease in which abnormalcells multiply without control, destroying healthy tissue and endangering life. Cancer occurs in most species of animals and in many kinds of plants, as wellas human beings. About 100 types of cancers attack human beings. BRCA1and 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 elderlypeople. It occurs equally among both males and females. The disease canattack 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 aredetermined 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 tocountry. For example cancer of the stomach is much more common in Japanthan in the United States. The primary body sites that cancer strikes mostoften 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 ofcells.

    Each minute, several billion of these die and are replaced severalbillion new cells. Each if these new cells then doubles in size and becomescapable of dicing throughout mitosis. This way, new cells are being producedfor every cell that dies. Normal, non-cancerous cells, divide at a normal raterequired 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 acontrolled rate. (Collins 183)Whenever anything interferes with the reproductive control of cells, thecells multiply and gradually build up a mass of tissue called a tumor.

    Tumorsthat are benign do not spread, while tumors that are malignant do spread anddestroy other parts of the body. The spread of cancer from one part of thebody to the other is known as metastasis. Cancer’s ability to spread makesthe disease extremely difficult to treat unless detected early. (Harris 4)Most experts agree that people develop cancer mainly throughprolonged contact with one or more carcinogens.

    In addition, scientistssuspect that a person may inherit a tendency to develop the disease as well,linking it to DNA alterations. Carcinogens attack normal cells and mayeventually cause one of the cells to become cancerous. Scientists believe that90 to 95% of cancer start this way. The changes are then passed on to thecell’s descendants. One cancerous cell turns into two, and two into four, andfour into eight, and so on.

    Carcinogens are introduced into the body throughthe nose, mouth, or some other bodily openings. Many cancers are caused bya combination of two or more agents usually rather than a single one. (Harris 7)Some cancers, including those of the breast and colon, occur amongblood relatives at a higher than average rate. Scientist believe that somepeople inherit a tendency to develop a certain type of cancer. Only a fewtypes of cancer though have been proven to be hereditary, such as, breast andovarian cancer. In addition researchers have identified certain genes, calledproto-oncogenes, that are vital to early tissue development.

    When thesegenes become changed or rearranged by chemicals or viruses, these genes intheir altered state are called oncogenes. The oncogenes than transform ahealthy cell into a cancerous cell. Scientists have identified over 50oncogenes that may cause cancer in certain organs such as the bladder,breasts, liver, lungs, colon, and pancreas. Some scientists believe thatoncogenes are involved in all cancers, while others do not. (Harris 7)Breast cancer is one of the most common types of cancer amongAmerican women, affecting 1 in 10 during their life time. It is estimated that45% of all families with significantly high breast cancer incidence, and atleast 80% of families with elevated rates of both early-onset breast cancer andovarian cancer, carry the mutated BRCA1 gene.

    A rough estimate is that 1 in200 women in the U. S may have an inherited mutation in the gene. (AmericanCancer Society packet) Up until the 1940’s many doctors and scientist thought breast cancerwas a result of old aging. Scientists know now that breast cancer is not aresult 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 necessarymeaning that they are all hereditary, but can be found linked to certain geneson chromosomes. (Love 165)Normal cells have 46 chromosomes which appear in 23 pair, butcancer cells usually have many more and on occasion fewer.

    The risks ofdeveloping breast cancer comes from either parent. Because each person hastwo copies of each gene, but transmits only one copy to each of his or heroffspring, the laws of chance predict that about half of all children of a parentwith a mutation in the BRCA1 gene will inherit the alteration. This flawedgene will make you more susceptible to cancer. The most common genes inwomen and men, that when damaged cause breast cancer are BRCA1 andBRCA2. BRCA1 and BRCA2 are also linked to an increased risk for ovariancancer as well as breast cancer. (Love 167)Usually breast and ovarian cancer are not inherited.

    It has beenestimated that about 5 to 10% of all breast and ovarian cancers are thought tobe due to mutations in a gene inherited from a parent. However, if anindividual has several closely related family members with breast and/orovarian cancer, or if cancer has occurred at an early age, there is highersuspicion 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 forthe normal functions of the cells.

    A mutation in BRCA1 can change theprotein it makes so the protein does not work as well. The BRCA1 gene isencoded by 5591 nucleotides distributed over a gnomic region which isapproximately 100kb in length. (Langston 3) SEE DIAGRAM 1It is possible that the BRCA1 gene may be involved in some sporadiccases through somatic mutations (mutations that cannot be passed tooffspring) that occur in DNA of breast cells during a woman’s lifetime. Preliminary evidence, however, suggests that BRCA1 plays a small role, ifany, 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 geneencode a protein of 1863 amino acids. The protein contains a putative RINGfinger domain near the amino-terminal, suggesting BRCA2 may regulatetranscription.

    (Levine 25) DIAGRAM 1BRCA2, 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 theestimated risk of ovarian cancer with BRCA2 is not as high as BRCA1. (Langston 3)When researchers isolated these gene, they looked at selectedindividuals with either breast and/or ovarian cancer. The researchers whoisolated the gene looked for BRCA1 mutations in 32 breast tumors and 12ovarian tumors from patients who were not known to be members ofcancer-prone families. From this test scientists found BRCA1 mutations inthree of the breast tumors and in one of the ovarian tumors.

    However, eachof the four was found to be a germline mutation, which suggests that thesepatients have inherited a BRCA1 gene mutation in the same way as womenfrom the families that have been studied. Future research will clarify ifBRCA1 has any role in sporadic breast cancers. Studies of families withinherited alterations in BRCA1 has suggested that more than half the womenwho carry a cancer associated mutation in the gene will be diagnosed withbreast cancer by age 50. (American Can Soc Pack 3)Since the isolation of these genes, studies characterizing the effects ofspecific mutations are presently being conducted. Existing tests to determinewhether a person carries a BRCA1 mutation are effected on both research oncommercial levels. Once the gene is identified in a family, researchers canlook directly for the specific mutation.

    This allows testing for familymembers to be much more easy, as well as less expensive. (Rizzler 24)In women who have been found to carry an altered BRCA1 gene, therisk to develop breast cancer by age 70 may be as high as 80. 5% and the riskfor ovarian cancer 40 to 60%. In other words, out of a 100 women whoinherit BRCA1 mutations, about 80 will develop cancer by the time theyreach 70 years; about 40-60 women will develop ovarian cancer.

    For womenwho develop cancer in one of the breasts, the risk is increased for cancer todevelop in the other breast as well. Men who carry a mutation in BRCA1 donot seem to have high risk to develop breast cancer, but there may be aslightly increased risk for prostate cancer or colon cancer. (Bre OvaPAMPHLET)We all have two BRCA1 and BRCA2 genes. We get these genes fromboth our mother and our father.

    A mutation in either of these genes can beinherited from either parent. If the mother or father does have a mutation theneach of his or her children has a 50% chance of inheriting the mutation. Chance determines who inherits the gene and who does not, and theappearance of the gene in one child has no effect on the risk in other childrenin the family. It is possible that all or none of the offspring of an affectedparent will inherit the mutated gene. (Scalia 1) SEE DIAGRAM 2BRCA1 and BRCA2 in their natural form, are thought to be importantfor normal function of cells.

    Because BRCA1 is a gene that has recently beenidentified, little is known either of its role in breast cancer development or itsnormal function. If there is a mutation, however, in either of these genes, orone copy of either gene is lost or damaged, its function may be disrupted,making breast cells and ovarian cells more prone to the susceptibility ofdeveloping cancer. Not everyone who inherits a mutation in BRCA1 andBRCA2 develops breast or ovarian cancer. BRCA1 or BRCA2 mutationdoes not cause cancer; however it does increase the chances for a person todevelop cancer.

    Scientists do not know why only some individuals with amutation develop cancer and why some do not, however, with the rapidprogression of cancer research and genetic testing these questions may soonbe resolved. (Scalia 1)Everyone has two genes of a specific trait. One from mom and onefrom dad. If one of these genes becomes mutated, or lost, then the other canserve as a break for the other and continue to function as normal. Womenwith inherited BRCA1 mutation are born with one bad copy, so that forcancer to occur they need only one additional damaging mutation in a breastcell some time during life.

    It is suspected that the BRCA1 and BRCA2 genesfunction as a tumor suppressor. Suppressor genes normally preventuncontrolled cell proliferation and their inactivation through mutation can leadto cancer. Inherited mutation occurs only on one gene, while the other is noteffected. Chances of that person developing cancer from one of these genesis greatly increased, i. e.

    85% breast cancer and 50% for ovarian cancer. (Scalia) SEE DIAGRAM 3 & 4One study published in the March 19, 1994 issue of the Lancetsuggested that more than 40% of women with a mutated BRCA1 gene maydevelop ovarian cancer. Also in this study, both male and female carriers ofBRCA1 mutations had significantly elevated risks of colon cancer, and malecarriers had increased risk of prostate cancer. (American Cancer Society)Only about half (45%) of all inherited breast cancers is due tomutations in BRCA1. About 35% is due to mutations in BRCA2.

    There maybe other genes which increase the risks for developing breast cancer as well. Scientists speculate there might even be a BRCA3 and a BRCA4 gene. Rightnow scientists do know of two other genes, tP53 and ATM, that might causea person to develop breast cancer; tP53 is involved in breast cancerdevelopment only when a person has the Li-Fraumency syndrome. Scientistsknow little about these genes and do speculate that ATM only effects thebreast tissue in combination with certain syndromes. (Cummings pg. 5)By studying normal cells and cancer cells under microscopes, cellbiologists have discovered important differences in the cell’s behavior.

    Theyhave found that during the process of mitosis, a series of carefullyorchestrated steps, normal cells continue dividing until they come in contactwith neighboring cells. Cell division then stops. This characteristic of normalcells is called contact inhibition. Cells that develop cancer have lost contactinhibition. They continue to divide even after they have come into contactwith other cells.

    (Kormanicky 56)BRCA1 and mRNA levels were found invariably low in tumors fromBRCA1 mutations carriers. As a tumor grows it needs nourishment. Thetumor sends out protein messengers called tumor aniogene factors to get thematerial it needs. Normal breast epithelium surrounding the BRCA1 tumorsshowed higher mRNA levels than tumor tissue, indicating that the low mRNAlevels were due to somatic inactivation of the wild-type BRCA1 gene. (Komanicky 56)Cell biologists have developed methods of destroying cancer cellswithout damaging healthy cells.

    They are also trying to learn howcancer-causing oncogenes are activated and how they can be turned off. Ifscientists learn how to deactivate oncogenes, they may find ways ofcontrolling the reproduction of a cancer cells. Such type of genes that may beable to turn off are BRCA1 and BRCA2. The process on how one would turnthese genes off is still not devised yet. (Myriad Genetics Patient pamphlet) When BRCA1 or BRCA2 mutation is inherited it is considered adominant factor. People receive one BRCA1 allele from their mom and oneBRCA1 allele from their dad.

    The same goes for any other gene pairs. BRCA1 is not just inherited by women, but men as well. It is NOT asex-linked trait. In order to study how organisms inherit genes, health careprofessionals use a Punnet square in order to understand how people inherit agene. Finding out if a person does have a BRCA1 or BRCA2 mutation isanother process. (Myriad Genetic Pamphlet) DIAGRAM 5Inherited alleles of family tumor suppressor gene predisposeindividuals to particular types of cancer; this is one of the reasons why canceroccurs.

    Doctors are still not sure what causes BRCA1 and BRCA2 genes tomutate. In addition to trying to find mutations on the BRCA1 and BRCA2genes, doctors are telling people to stay healthy in order to decrease aperson’s risk of cancer. Some mutations not on BRCA1 and BRCA2 stop thegene from functioning, while others force genes to create abbreviated ormisshapen molecules (proteins) that function incorrectly. (Travis 374)The risk of harboring a mutation is not limited to women who have afamily history of breast or ovarian cancer. Results of this represent a minimalestimate of the frequency of BRCA1 mutations. Right now scientists havefound over 100 distinct germ-line mutations of BRCA1 that have beenidentified in more than 100 patients with breast/ovarian cancer.

    A recentcollaborative survey describing 80 germ-line mutations summarizes thespectrum and frequency of BRCA1 mutations identified to date primary in thehigh-risk families. (Langston 3)No somatic mutations of the BRCA1 or BRCA2 genes have beenidentified in sporadic breast cancers, though 5 mutations have been found insporadic ovarian tumors. This suggest that BRCA1 is primarily a germ-linemutation. (Gaithersburg 1)The outcome of BRCA1 mutations may reflect the different duties thegene’s protein performs in breast and ovarian cells. Scientists think thatthere are only 3 main types of mutations on BRCA1.

    Additional mutationshave been found twice by a complete screening of the cDNA. The totalpercent of a recurring mutations is 31%. (Davison www. cancer. org)Inherited mutations on BRCA1 and BRCA2 are known to contribute toa predisposition to breast cancer. Heterozygotes for mutations in theataxia-telangiectasia gene also increases a woman’s risk for breast cancer.

    Females who are obligated carriers of ataxia telangiectasia have a 4 to 12times increased relative risk of developing breast cancer as compared to thegeneral female population. Increasing their overall chances of developingbreast cancer. (Anderson 408)Mutations in the BRCA1 gene are identified through a highly technicalprocess; the sequencing of DNA obtained from a blood sample. CurrentlyMyriad Genetic Laboratories is testing individuals under clinical researchprotocols with institutional review board approval.

    The decision to be testedmust be made by the individual, in consultation with a healthcareprofessional. Those who may benefit form the BRCA1 genetic susceptibilitytesting include: (American Can Soc 13)~women who have been diagnosed with breast cancer, especially thosewith early onset-disease. ~women who have been diagnosed with ovarian cancer. ~women with a family history of either breast or ovarian cancer. ~women who are blood relatives of those who carry a BRCA1 mutation. ~men who are blood relatives of those who carry a BRCA1 mutation.

    If the family history of a woman with breast/ovarian cancer is uncertainor unknown, testing may still be appropriate. For example, she may have fewfemale relatives or, since men also have a 50% chance of passing themutation to each of their offspring, the susceptibility may have been passedthrough her paternal line. These and other factors need to be considered inthe woman’s decision to be tested. (Ovarian Cancer Pamphlet)Early cancer detection provides the best opportunity for reducingmortality for all women. Women who test positive for BRCA1 geneticsusceptibility may benefit from increased surveillance. Some healthcareprofessionals are prescribing earlier implementation and more frequentutilization of the following surveillance methods: (Ovarian Cancer Pamphlet)Breast cancer detection guidelines:~breast self-exams.

    ~clinical breast exams. ~mammograms. ~consultation with a qualified healthcare professional if a change in breast tissue is detected. Ovarian cancer guidelines:~CA-125 serum tumor marker testing~transvaginal ultrasound~rectovaginal pelvic examinationWomen who have a BRCA1 mutation and have been diagnosed withbreast cancer are at an increased risk of developing cancer in the other breast. This may affect treatment decisions, i. e.

    , the choice between a mastectomy ora lumpectomy of the affected breast, and either prophylactic mastectomy ofthe unaffected breast and/or prophylactic oophorectomy. (Doctor Pamphleton breast cancer/Gaitherburg)Ways to treat breast cancer:~Prophylactic oophorectomy. Many clinicians believe that this is thetreatment of choice for the women who carry BRCA1 mutation or for thosewho have a strong family history of breast cancer. A bilateral removal of theovaries to decrease estrogen production is effective as well.

    Otherconsiderations include the individual’s risk for cardiovascular disease andosteoporosis and her concerns about sterility. (Doctors Pamphlet on BRCA1and 2)~Prophylactic mastectomy. Because dense breast tissue may interfere withthe clinical examination and mammography, and in premenopausal women every breast cell has a mutated gene placing a woman at a 95% risk duringher lifetime for breast cancer, the volume of the breast tissue that can beaffected is reduced through mastectomy, making prophylactic surgeryappropriate for women who carry a BRCA1 mutation. However, becausesurgery cannot remove all breast tissue, the risk of developing breast cancercannot be totally eliminated.

    (Doctors Pamphlet on BRCA1 and 2)Another kind of treatment is hormone replacement therapy. Hormone replacement therapy has been shown to be effective in relievingsome of the conditions often associated with menopause, as well asdecreasing the risk of a heart attack and osteoporosis. However, the use ofreplacement hormones may increase the risk of breast and endometrialcancer. Post menopausal women who are currently taking hormones(estrogen or a combination of estrogen and progesterone) have a relative riskof 1. 46% of developing breast cancer compared to post-menopausal womenwho have never taken hormones or had breast cancer.

    The effect of hormonereplacement therapy for shorter periods of time and for women who carry amutated BRCA1 gene is currently unknown. (Gayther 1462)There are some life modifications that women can make in order todecrease their chance of breast cancer. Women who carry a BRCA1mutation should be encouraged to evaluate their current lifestyle habits and, ifnecessary and/or appropriate, modify the following: (Gross 88)Age at first pregnancy: Data indicates that women who deliver theirfirst child before age 30 are less likely to develop breast and ovarian cancer. Body weight: individuals who are 40% or more over- weight mayhave an increased risk of breast and ovarian cancer.

    In addition, maintainingdesirable body weight increases efficacy of cancer screening procedures. Exercise: Physical activity during a woman’s reproductive yearsaffect the production of estrogen and other sex hormones. This may providea protective effect against breast cancer risk. Tobacco use: A study indicates that a woman’s risk of dying frombreast cancer increases 25% if the women smokes cigarettes.

    Diet: Some studies suggest that eating a balanced diet has ananti-tumor affect. Recommendations for a balanced diet include foods low infat and rich in fiber and antioxidants; green leafy vegetables; soy products;and broccoli, cabbage, brussel sprouts, and other cruciferous vegetables. Alcohol: Some studies indicate there is some link between alcoholconsumption and the development of breast cancer, although no causalrelationship has not been proven. (Gross 89) SEE DIAGRAM 6In the future, scientists hope discoveries will lead to gene therapy, butfor now there is little one can do about a genetic predisposition beyondcounseling and lifestyle changes. The BRCA1/BRCA2 genetic susceptibilitytest is commercially available through Myriad Genetic and OncorMedLaboratories.

    Testing to verify sensitivity, specificity, and other parameterswill commence at cancer centers throughout the U. S. Educational materialswill be provided to healthcare professionals who offer BRCA1/BRCA2testing to assist in presenting and discussing issues with patients both beforeand after the test. (Breast/Ovarian Pamphlet)Having a test for either BRCA1 or BRCA2 could affect a person’sability to get or to keep insurance in the future.

    If a mutation is found insomeone’s family that increases the risk for developing cancer, it could affecttheir family’s ability to get or to keep insurance (health, life, and disability). One may experience loss of insurance, inability to qualify for new insurance,increased premium payments, or decreased coverage. A person may belocked into a job to keep coverage, or lose coverage in the event of a job loss. (Hereditary Breast Cancer 4)Patients should talk to their doctor about how the information will bekept in their medical record.

    People who are concerned about how their testresults will be used need to consider paying for tests out of their ownpockets. Legislators are in the process of introducing state bills which bansuch discrimination from employers and insurance companies. Twenty statesalready have statutes that, to varying degrees, protect the confidentiality ofgenetic test results and protect them from employment or insurancediscrimination. The presence of a mutation in BRCA1 or BRCA2 indicates that thereis a risk to develop cancer. It does not mean that cancer will definitelydevelop.

    Although testing is very accurate, there is a chance that an inheritedmutation in BRCA1 or BRCA2 will not be detected or that a mutation existsin another gene for which testing was not done. Cancer can and does occurfor other reasons. . .

    (Hereditary Breast Cancer 4)There are psychological risks for being tested. Some people may alsohave difficulty in knowing that they carry a gene which increases their risk todevelop breast cancer. They may experience emotions, such as: anger,denial, anxiety, or shock; fear of cancer or of the future; worry about theirhealth, family, employability; changed self-image; guilt for possibly passingthe gene to children; worry about the future medical costs and insurability. These are all normal reactions. (Hereditary Breast Cancer 4)If a mutation in BRCA1 and BRCA1 is found, one will be encouragedto inform other family members who may also carry the mutation. In theprocess, other family members may also find out confidential information.

    For example, someone may disclose that a family member is adopted. Therefore, sometimes relationships in families may be affected. (HereditaryBreast Cancer 4)In conclusion, it is believed that 1 out of 3 women will inherit breastcancer during their life time, though others may disagree. Undoubtedly breastcancer is a silent killer in which it must be detected early in order to beprevented or stopped. As one person put it, ?This is the most exciting andmost frightening time there is in the research of breast cancer. ? BibliographyBIBLIOGRAPHYAnderson, Greg.

    50 Essentail Things To Do When The Doctor Says It’sCancer. Middlesex: Plume Publishers, 1993. Beckman, M. W. ?Clinical Impact of Detection of Loss of Heterozygosity ofBRCA1 and BRCA2 Markers in Sporadic Breast Cancer.

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    ?Hereditary Breast Cancer: Questions and Answers for Physicians. ?OncorMed Inc. Gaithersburg, August 1996: 1-8. Ivor, Benjamin. ?The Breast-Ovary Cancer (Pre-clone). ?Available www.

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    ?BRCA1 Mutations In A Population? New EnglandJournal of Medicine. 18 January, 1996: 334-344. Levine, Joseph, and David Suzuki. The Secret of Life Boston: WGBHEducational Foundation, 1993. Love, Dr.

    Susan. Dr. Susan Love’s Breast Book. Canada: OTA Publishing,1995.

    Malone, Kathleen. ?BRCA1 Mutations In A Population-Based Sample ofYoung Women With Breast Cancer. ? The New England Journal of Medicine. 18 Jan, 1996: 136-137. Michnovicz, Jon. How to Reduce Your Risk of Breast Cancer.

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    com/dg/z9d. ehtm26 Sept. ,1996. Offit, Kenneth. ?Germline BRCA1 185delAg Mutations in Jewish WomenWith Breast Cancer.

    ? The Lancet June 15, 1996: 1643. Rizzler, Carol Ann. Estrogen and Breast Cancer New York: MacMillan,1993. Robinson, Rebecca, and Jeanne Petruck.

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    1997. Sirsky, Joan. Breast Cancer Handbook. New York: Harper CollinsPublishers, 1994.?Why Clone Animals for Use In Cancer?’science Year 1995, 1995 ed.Science Essays

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