Breast cancer is the most common cancer that affects women in the United States. There are at least two majors genes (BRCA1 and BRCA2) that when they mutate can cause breast cancer. These genes can be passed from parent to child, increasing the risk of developing cancer in those child that have parent carrying these genes. BRCA1 and BRCA2 genes are located on chromosome 17 and chromosome 13 respectively. There is a 90% chance of developing breast cancer for a woman that has these mutated genes. In contrast, men carrying BRCA1 have no risk to develop breast cancer, but those carrying BRCA2 genes have high risk. It is important to note that mutations in these genes can be passed on to children by either parent. A man with a mutation is just as likely to pass this gene to his children as a woman with a mutation. Hereditary cancer occurs at young age, for instance a woman in her 20's with breast cancer is more likely to have hereditary type of cancer that a woman in her 50's. (http:www.familycancer.org/FamHist.stm)
BRCA1 and BRCA2 are tumor suppressor genes, these genes also called "Anti- Oncogenes" which normally are involved in regulating cell growth, the proteins inhibit the proliferation of cell, which is crucial for the normal cell development and differentiation. (Britanica on line).
Since the discovery of the BRCA1 and BRCA2 in 1994 and 1995 about 80% of the women who inherit mutated forms of these genes will develop breast cancer in their lifetime, usually at relatively early age and woman with BRCA1 mutations have a high risk of developing ovarian cancer as well.
Kudson in 1971 proposed a two-mutation theory of cancer causation. His theory stated that all cancer are of two kind, hereditary and sporadic In the case of hereditary cancer, at the time of fertilization, the zygote (the fertilized egg) receives a imperfect copy of a gene (mutation). Subsequently, each cell that develops from the fertilized egg will receive this mutated gene. He states that for a cancer to manifest, two mutations must occurs. In hereditary cancers, the person inherit one mutant gene. The second mutation occurs as result of a mitotic error during the many cell division that occurs in the person's lifetime. In sporadic cases both mutation occur in the person's lifetime. In sporadic cases both mutation occurs after fertilization an are acquired much later in life. From this Kudson conclude that hereditary cancers manifest at younger age and there is a higher incidence of multiple tumors, where sporadic cancers occur late in the life and usually only a single tumor occurs. The principal causes of cancer appears to be environmental agents. A good example of this is skin cancer. The condition has increased among fair skinned people who expose themselves to too much sunshine, while being very uncommon among dark skinned races (knudson 1971, cited in Ormiston, 1995). Therefore, most genetic alteration are acquired through our life time from environmental carcinogens with only a small percentage been inherited. However, inherited cancers are very important as it appears that the genes responsible for, hereditary cancer maybe the same as those involved in sporadic malignancies.
There are two important type of genes responsible for the development or cancer namely tumor suppressor because their normal function is to suppress cell growth. The inactivation of these genes lead to uncontrolled cell growth. The oncogenes are responsible for the promotion of cell growth. Mutation of these genes cause a uncontrolled growth. The development of cancer due to an inherited risk is not though to occurs through this mechanism (Ormiston, 1995).
In September 1994, a new breast cancer susceptibility gene. BRCA2, was identified on chromosome 13q and BRCA1 on chromosome 17q, which had been identified in 1990, was sequenced. Given the current stage of knowledge it is felt that these two genes together account for at least two thirds of familial breast cancer or roughly 5% of all cases. BRCA1 is also associated with the predisposition to ovarian cancer. Analysis of more than 200 families worldwide has shown that the BRCA1 gene is probably linked to on third of families who present with multiple cases of breast alone, but more than 80% of families in which there are both breast cancer and ovarian cancer.. The life time risk of breast cancer in BRCA1 mutations carriers is about 70% by the age 70 years. In ovarian cancer the lifetime risk is approximately 40%. BRCA1 is believed to be a tumor suppressor gene (Ormitom, 1996).
BRCA2 is believed to be equal in importance to the BRCA1 gene. There are however, differences in these genes. The high incidence of ovarian cancer-linked to the BRCA1 gene, but the BRCA2 gene is associated with very low incidence of ovarian cancer. No male breast cancer cases have been seen in the BRCA1 family sets, whereas several cases are present in the BRCA2 families. To date linkage of these two genes has not been proven for all families with inherited predisposition to breast cancer, so further genes conferring inheriting risk remain to be discovered (Brody and Bowles,,1998).
Breast cancer is far the most frequently diagnosed neoplasm in women. Each year, over 186,000 new cases and 46,000 death are reported in the United states alone. The majority of breast cancer diagnosis occurs late in life (postmenopausal) and no strong inheritance factor or gene mutation are present. A number of risk factors for the development of breast cancer have been identified. Non-genetic risk factors include age of menarche, menopause, and first child birth. Early parity and menopause appears to decrease risk, while early menarche correlates with an increased risk. Risk is also found to increase with a positive breast cancer family history, presumable due a genetics factors. Mutation in susceptible genes of high penetrance such as BRCA1 and BRCA2 is estimated to account for 3% to %5 of all breast cancer. It is now estimated that two independent loci, BRCA1 and BRCA2, are likely to account for the majority of inherited cancer cases. In this case cancer susceptibility is inherited in autosomal dominant manner. Men and woman who carry a mutation in one of these genes have a 50% chance of passing it on to each of their children (Brody and Bowles,,1998).
Initial penetrance estimates for BRCA1 and BRCA2 mutation have been generated from high risk families. Data from the breast cancer Linkage Consortium families predict that woman carrying a BRCA1. Mutation have approximately an 80% lifetime risk of breast cancer . Even though this estimates are corrected, it is possible that penetrance of mutation in the context of high risk families is influenced by other factors. Accurate penetrance estimates are important component in the process of clinical risk assessment . Knowledge of factors that modify penetrance will be require before risk reduction and cancer prevention treatments designed to BRCA1 and BRCA2 mutation carriers can be developed. (Brody et al., 1998).
Allan Bradley' group at Baylor college of Medicine in Houston, report evidence that the protein made by BRCA2 play a critical role in enabling cells to repair their DNA when it damaged. The group find, for example, the BRCA2 binds to a known repair protein called RAD51, There has been another report that suggests BRCA1 protein also associates with these proteins. Possibly both genes are part of the same DNA repair pathway. The genes were originally considered to be classical tumor suppressor, which normally hold cell growth in check and which, if inactivated, can lead directly to cancer. But the new work suggests the mutations act indirectly, by disrupting DNA repairing and allowing the cell to accumulate mutations including those that foster cancer development (Science vol.276, 1997).
BRCA1 and BRCA2 are unrelated at the sequence level, recent research has reveal similarities between them. First, both contain a region that can act as a transcriptional activation domain when is it fused with the DNA binding domain from another gene. Naturally occurring mutation found in both BRCA1 and BRCA2 in breast cancer families can compromise this transcripcional activation. As a transcriptional factor are often found among the gatekeeper class of cancer (Gatekeeper are genes that directly regulate the growth of tumors by inhibiting growth or promoting death.) This properties indicates that BRCA1 and BRCA2 may directly control cellular proliferation. Moreover, BRCA1 can inhibit the growth of cell in which it is over expressed. There is also a link between an inhibitor of cell cycle dependant kinase and the BRCA1 protein.
The second similarity is that both BRCA1 and BRCA2 bind to Rad5 protein that is involved in maintain the integrity of the genome (Kinzler et al, 1997).
A mutation in the AT, or ATM, gene on chromosome 11 also is associated with breast cancer, and it may be much more common in the general population than BRCA1 or BRCA2 mutations. Seven percent of familial breast cancer may be associated with the AT gene mutation (Radford and Zehnbauer, 1996, cited in McCain, 1997). It is not known whether the AT mutation increases the risk of breast cancer for men. Ataxia teleangiectasia is an autosomal recessive neurologic syndrome. The cancer incidence among those people who inherit two copies of the AT mutation, and who are affected by Ataxia teleangiectasia syndrome, is 100 times greater that the general population. Women who have inherited one copy of the mutation (approximately 1.4% of the general population) may be more susceptible to breast cancer.
Women with mutations in the p53 gene also may be at increased risk of developing breast cancer. However, mutations of the p53 gene are rare, affecting an estimated 1 in 10,000 individuals (Athma et al., 1996 cited in McCain, 1997).
Mutations in HRAS1, the Cowden disease gene, p65, and TSG101 may also confer a higher risk of developing breast cancer (Easton et al., 1993; Krontiris et al., 1993; Greene, 1997 cited in McCain, 1997).
BRCA1 and BRCA2 mutations and breast cancer seem to be distributed among a variety of populations. Several studies indicate that the Ashkenazi, a population of Eastern European Jews, may have a higher proportion of BRCA1 and BRCA2 mutations than the general U.S. population (Struewing et al., 1997; Levy-Lahad et al., 1997; Egan et al., 1996). ( Britanica on line).
Recently, it was discovered that in the Ashkenazi Jewish population a single BRCA1 mutation called 185delAG is commonly seen in breast and ovarian cancer families. Preliminary studies have shown that about 1% of Ashkenazi Jews carry the 185delAG mutation. This genetic alteration has been estimated to account for 20% of cases of breast cancer and 39% of ovarian cancer diagnosed in Jewish women before age 50. In addition, two other BRCA1 mutations, 188del11 and 5382insC, seem to be overrepresented in the Ashkenazi Jewish population.
A specific mutation in BRCA2 (6174delT) has been identified in Ashkenazi Jewish women with early onset breast cancer. The 6174delT BRCA2 mutation is approximately as common as the 185delAG BRCA1 mutation, and the 5382insC mutation is about half as frequent as the 185delAG. These results indicate that approximately 1 in 40 Ashkenazi women may carry one of these three BRCA mutations. This current data also implies that hereditary breast cancer may account for at least 15-20% of all breast cancer in Ashkenazi Jewish women.
A recent multi-institutional study of 235 Jewish individuals from families with high frequencies of breast or ovarian cancer found either the 185delAG, 5382insC or 6174delT mutations in 43% of patients. Even more remarkable are data regarding a series of Ashkenazi women with ovarian cancer who were NOT selected for family history, age or other criteria. Results of DNA testing for 185delAG, 5382insC or 6174delT showed that 36% of these women were positive. This information, along with other data, indicates that genetic testing for mutations of BRCA1 and BRCA2 has a significant role in clinical management and counseling of high risk Ashkenazi Jewish families.(http://www.givf.com/brca1.html).
It is generally accepted, that woman who are at increased risk of hereditary breast cancer require intensive surveillance. Mammography and annual clinical breast examination is standard practice from age 35 years onward or from 5 years before the earliest onset of breast cancer in family (Evans et al 1994). However is unclear if mammography in women under the age of 50 year is effective because of the increased density of the breast tissue in premenopausal women. There is concern also about the accumulative radiation dose with repeated scan in women already genetically predispose to breast cancer. Clinical and breast self examination are recommended. (Ormison, 1996)
Another drastic attempt to reduce the risk of breast cancer to woman who have very high risk of the disease is bilateral prophylactic mastectomies, but there is no epidemiological data which supports the theory that removing breast tissue and ductal cells completely removes the breast cancer risk. The best clinical management involves asking the woman concerned to consider several factor in making a choice for or against surgery. These include her individual risk, how difficult her breasts are to examine by mamography and physical examination, and her attitude to living with extremely high risk, versus the emotional and physical consequences of breast surgery with unknown remaining risk.
There may be a genetically inherited component to some breast cancers. For example, inherited genetic mutations to BRCA1 and BRCA2 seem to confer an increased risk to developing breast cancer for some people. However, not all familial breast cancer is inherited. In fact, inherited genetic mutations may contribute to only 5% to 10% of all breast cancers. Nor does the presence of genetic mutations accurately predict the development of breast cancer, when cancer might occur or with what severity. Families also share many environmental and cultural similarities that may affect their risk of developing breast cancer and other diseases. Medical researchers don't know all the factors that contribute to developing cancer but have isolated some potential risk factors (besides genetic mutations) that appear to increase the chance of developing cancer. These include a diet high in fat and calories, smoking, exposure to environmental toxins and pesticides, exposure to various hormones, lack of exercise, exposure to sunlight, and some other kinds of radiation. Like genes, cultural behaviors are passed on from generation to generation within families. Our patterns of diet and exercise are good examples. Members of families live together in the same community, sharing the same water supply, foods and environmental exposures. Breast cancer may result from a combination of two or more of these cultural and environmental factors, or in combination with certain genetic mutations. The occurrence of breast cancer in families also can be coincidental.
The interaction between cultural behaviors, the environment and a person's genetic makeup makes it difficult for health-care professionals to determine what part genetic mutations play in understanding how breast cancer can develop in several members of the same family. Researchers hope the social and medical sciences working together will be better able to explain the interaction of genes, culture and environment in the near future. The prevention and treatment of breast cancer will depend upon the knowledge provided by both sciences. (http://www.ncgr.org/gpi/odyssey/BCAN2/fambc.html).
Soon after the discovery and cloning of the BRCA1 and BRCA2 mutations, companies and research laboratories began offering genetic testing for people interested in knowing whether they were carriers of these mutations. However, genetic testing for BRCA1 and BRCA2 is controversial. Tests may not provide information useful to test recipients; they cannot predict who will get breast cancer or how severe its manifestations might become. Tests can tell the customer whether he or she carries the mutation, but what preventive treatments are available?
Information from tests can do more harm than good. Clients who discover they have a mutation can be vulnerable to insurance and employment discrimination. They may also experience depression and other psychological and social stress while waiting to see whether the disease develops and the disease may never develop.
For these reasons, many groups and individuals oppose genetic testing for breast cancer mutations. Supporters believe these concerns can be minimized if potential consumers are educated about the limits of tests and their potential consequences. In most cases, tests are offered only to people with strong family histories of breast cancer who have undergone pre-test counseling and education ( http://www.ncgr.org/gpi/odyssey/BCAN2/gtest.html).
I think the genetic counseling is a way to understood the nature of the disease, severity, prognosis and, whether or not there is an effective therapy, but the amount of information need it depend of each person. The alternative of breast cancer gene testing should be offered only a woman with a strong family history of breast cancer, because if she carries the mutation will benefit from a strict surveillance and monitoring or from a bilateral mastectomie, and also avoid in same degree the pain suffered by her relatives that were not diagnosed earlier in their life.
I believe that one of the most difficult thing in life is confront our own mortality and this test make us aware of it. But also provide the relief from anxiety if the result is negative, but if the opposite result means that is a high probability to develop cancer and also pass the defective genes onto our children, and take a lot of courage to overcame the negative attitude that the result can lead.
2.-Ormiston W. 1995. Hereditary breast cancer. European Journal of Cancer Care. 5, 13-20
3.-Social and Ethical issues of breast cancer gene testing. Obtain from http://www.ncgr.org/gpi/odyssey/BCAN2/gtest.html 10/29/98
4.-Kinzler, Kenneth W., and Vogelstein, Bert. 1997. Breast cancer susceptibility genes BRCA1 and BRCA2. Nature. V. 386. 761-763.
5.-Marx, Jean. 1997. Possible function found for breast cancer genes. Science vol.276. 531- 532.
6.-McCain, L., and Dilligham, C., 1997. Genetics Mutation Associated with Breast Cancer . Obtain from http://www.ncgr.org/gpi/odyssey/BCAN2/genrisk.html 10/12/98
7.-Tumor suppressor gene" Obtain from http://www.eb.com:180> 10/19/98, search word: tumor suppressor gene.
8.-Breast and/or ovarian cancer risk in Jewish women: Role of the 185delAG and other mutations in the BRCA1 and BRCA2 genes. http://www.givf.com/brca1.html 10/12/98.