Breast Cancer Susceptibility Screening

Roxy R. Mickelson

Copyright 1997


In 1994, researchers isolated a gene, BRCA1, that has had an unprecedented impact on the study of cancer genetics. BRCA1 is a breast cancer susceptibility gene, meaning that women who possess certain mutations in this gene also possess a greatly inc reased risk of acquiring familial breast cancer. Just a year later, a second breast cancer susceptibility gene, BRCA2, was discovered. Mutations in these two genes alone appear to be responsible for approximately 70% of breast cancer cases in families w ith an inheritance pattern affecting several generations.

Due to the impressive statistics and the potential to alter the lives of millions of women, BRCA1 and BRCA2 have continuously been the focus of intensive research in laboratories around the world. Research has led to the development of genetic scree ning techniques to detect possible cancer-causing mutations. Along with the evolution of screening techniques, however, has come public scrutiny. The ethics of genetic testing for breast cancer must be examined as a critical aspect of the issue. In thi s paper, I am going to discuss the following areas pertaining to the topic of breast cancer susceptibility screening:

Concepts in Cancer Genetics

The human body contains two major classes of regulatory genes that are necessary for normal cell growth control. These classes are proto-oncogenes and tumor suppressor genes. Proto-oncogenes code for proteins such as peptide growth factors and nu clear transcription factors that control cell division and DNA synthesis. When proto-oncogenes are activated by either point mutation, amplification, or translocation, they become oncogenes. This activation step often leads to uncontrollable cell growth and formation of tumors. Even so, proto-oncogenes are rarely involved in breast cancer and other hereditary cancers. The second class of regulatory genes, tumor suppressor genes, code for proteins that restrict uncontrollable cell growth. They can be inactivated through loss of expression, deletion, or mutation. Such mutations have the ability to be passed from generation to generation, producing an inherited susceptibility to cancer. Both BRCA1 and BRCA2 are believed to be of this second type, tumo r suppressor genes. As a result, they inhibit tumor formation when functioning normally but cause a predisposition to breast cancer when mutated.


As already mentioned, BRCA1 was the first breast cancer gene to be isolated. This was accomplished through positional cloning methods. BRCA1 is located on the long arm of chromosome 17 and encodes a large, negatively charged protein. A woman who c arries an inherited mutation in BRCA1 has a greater than 80% chance of developing breast cancer at some point in her life. The risk for women in the general population who do not carry a mutation is only 10%. It is important to note, however, that breas t cancer is not inevitable just because a woman is a carrier for a mutation. More than 100 unique mutations in BRCA1 have been identified thus far, most of which are either nonsense mutations, deletions, or insertions. The high number of mutations in th is gene alone demonstrates the complexity of the genetic screening debate.

BRCA2 is located on the long arm of chromosome 13 and, like BRCA1, codes for a large, negatively charged protein. A woman who carries a BRCA2 mutation possesses an increased risk for breast cancer that is similar to that for BRCA1. The BRCA2 mutati ons are dispersed throughout the coding region, with a proportionately high occurrence of insertions and deletions in relation to BRCA1. I should also note that both breast cancer genes, particularly BRCA2, are also implicated in the inheritance of ovaria n cancer.

Screening Techniques

I will now discuss the technical aspects of genetic screening for breast cancer by presenting the major techniques used, how these techniques differ, and which ones are currently the most promising. First of all, one might ask why, with the existenc e of diagnostic tools like mammograms, is genetic screening for breast cancer even necessary? The answer is simple: Mammography and genetic screening are two entirely different methodologies. Mammography is a procedure offered to the general public base d on gender and age, is relatively inexpensive, and whose main goal is to provide early detection of breast cancer. Genetic screening applies only to high risk individuals, is much more expensive, and whose main goal is only to determine risk of developi ng breast cancer at some point in a woman's lifetime. The discovery of mutations through genetic screening does not guarantee that a woman will ever develop the actual disease. In contrast, a positive mammography indicates that a tumor is already presen t in the body. Many tumors are already very large by the time they are even detected through a mammogram.

The major obstacle in developing successful screening techniques involves the size and complexity of breast cancer genes. BRCA1 and BRCA2 are both very large genes with many exons and a substantial number of different mutations. It is inconceivabl e that one test could detect every possible mutation. Also complicating the issue is the continuing discovery of additional genes that may be involved in breast cancer susceptibility. The techniques I will discuss here pertain only to BRCA1 and BRCA2, b ecause researchers have the most knowledge about these particular genes.

Genetic screening techniques are grouped into two main categories: screening and scanning methods. Screening methods involve probing the gene for previously identified mutations. These methods are unrealistic for use in breast cancer due to the ex istence of so many mutations throughout the gene. Mutations can be found virtually anywhere within BRCA1 and BRCA2, including both coding and non-coding regions. Development of a separate DNA probe for each mutation is simply too expensive and time-cons uming to make screening methods feasible at this time.

Scanning methods involve scanning the gene with no presumptions about existing mutations. The major limitation with scanning methods is that only the promoter region, coding regions, and splice sites are incorporated. Mutations in regulatory region s other than the promoter and in introns are overlooked. Of the mutation scanning methods that exist, four are relevant with respect to breast cancer. These are 1) nucleotide sequencing, 2) chip technology, 3) test of molecular phenotype, and 4) protein truncation tests.

Nucleotide sequencing is currently the standard against which other methods are compared, due to its extremely high accuracy. However, this method is also very laborious and expensive. In light of these factors, performing nucleotide sequencing on genes as large as BRCA1 or BRCA2 is not feasible.

Chip technology involves impregnating a wide variety of DNA sequences onto a small glass slide called a microchip. The DNA sample from the woman who is being tested is then compared to these variants through hybridization analysis. This method has a potentially high accuracy, but its general usefulness has yet to be proven. This method is suitable for a confined set of mutations in BRCA1.

Test of molecular phenotype consists of analyzing a gene for a particular molecular phenotype. This method is not very suitable for breast cancer susceptibility genes because the exact functions of these genes are not yet known.

Finally, protein truncation tests use fragments from polymerase chain reaction (PCR) as templates to yield protein products. Gel electrophoresis is then utilized to expose a truncated protein that is coded for by mutated forms of the gene. Advantag es to this method are the relative quickness with which it can be performed, along with low cost. Disadvantages include the fact that this method is RNA-based rather than DNA-based; also, missense mutations cannot be detected. The accuracy of protein t runcation is highly variable depending on the particular gene, its array of mutations, and its biology. Current data estimates that more than 99% of BRCA2 mutations are truncated forms of the gene. If this is true, then protein truncation tests are cur rently the most promising method for determining breast cancer susceptibility.

An ideal genetic test for breast cancer would conform to the following criteria:

Ethical Considerations

Advocates of genetic screening believe that genetic screening results in 1) better understanding, 2) peace of mind, and 3) time to prepare. Genetic testing, especially within a research setting, may lead to increased knowledge about diseases like breast cancer. This information could eventually lead to more successful treatments and possibly even a cure. Secondly, a woman who finds out she does not carry mutations in breast cancer genes may experience a renewed sense of peace and be able to save her relatives from having to go through expensive testing procedures also. Finally, advocates of genetic testing believe that it is to a woman's benefit to know if she has genetic mutations or not, thus giving her time to prepare. A woman who tests posi tively may be more likely to make lifestyle changes and take control of her life with increased mammograms and check-ups with a physician.

Critics of genetic screening believe it is unethical due to 1) uncertainty, 2) psychological impact, 3) false sense of security, and 4) potential for discrimination. The claim of uncertainty revolves around the fact that just because a woman tests p ositively does not mean she will eventually develop breast cancer. Likewise, a woman who tests negatively may still be at risk due to other factors such as age, reproductive health, and environmental influences. Secondly, the psychological effects that genetic testing may have on women is a concern. Critics believe that a woman who tests positively for mutations may undergo intense psychological stress and depression, even though there is not a 100% guarantee that she will eventually be stricken with b reast cancer. Only one major study has actually assessed the psychological impact of genetic screening. The results of the study showed that one month after genetic screening, the psychosocial scores of women who tested positive made no substantial chan ge for better or for worse. A false sense of security may result if a woman tests negative for mutations and then believes she is not at risk of ever acquiring breast cancer. Many factors other than genetics influence risk of breast cancer, and genetic testing results have to be analyzed with respect to those other factors. Also, many physicians are not well trained in the field of genetics and may not know how to accurately interpret test results. Finally, critics of genetic screening are concerned t hat employers and insurance companies may use test results to discriminate against people who possess an increased risk of disease.

Public Policy Reactions

Genetic discrimination is perhaps the most critical ethical issue involved because the idea of discriminating against someone due to their genetic makeup is a very new concept. Fortunately, this is an issue that has recently been regulated. Public policy steps have been taken in the hopes of preventing genetic discrimination. The Health Insurance Portability and Accountability Act of 1996 mandates that: This law is a definite step in the right direction, but people on both sides of the issue believe that further legislation is needed to fully protect at-risk individuals.

Personal Views

Personally, I feel that genetic screening for breast cancer susceptibility is an incredible advance in the field of cancer genetics, but it does have limitations. The only way that genetic screening can be successful is if patients are fully informe d. Women must be educated by trained professionals about what both positive and negative test results do and do not mean. Physicians need to be more highly trained in areas of genetics so they can provide women with the information they need to make ed ucated, informed decisions about their health. Women also need to be informed of the impacts that testing results might have on their family, their psychological well-being, and their future.

I think that advocates and critics of genetic screening have valid arguments. What is overwhelming to me is the fact that a woman can have a test and, even if the results of that test are accurate, her future is still uncertain. A woman who tests n egative could easily develop breast cancer the next year due to a host of factors other than BRCA1 or BRCA2 mutations. Likewise, a woman who tests positive may undergo needless psychological strain and never develop breast cancer. Basically, I think tha t genetic screening for breast cancer should only be undergone by women who do have a strong family history of breast cancer, who are given the resources to make an informed decision, and who fully understand the implications of test results.

I consider myself lucky, because I do not have a history of breast cancer in my family. If I did, however, I would not subject myself to genetic screening mainly due to the uncertainty of results.


With the discovery of BRCA1 and BRCA2 and the continued efforts going into discovering new cancer genes, the way society views and accepts cancer is changing dramatically. Although the current genetic tests are far from perfect, they open up a whole new door into the future. Many people probably feel there will never be a cure for breast cancer, but I truly believe that the hope for a cure will become a reality. Science has progressed so rapidly in cancer detection and prevention, hopefully someda y cancer will not be viewed as an inevitable death but rather as a minor obstacle on the road of life.


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