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This report originally appeard on the Sapient Health Network web site, which later became WebMD.

The Role of Genetic Mutations in Breast and Ovarian Cancer 

By Andrew Holtz 

Feb. 1998

The discovery of genetic mutations that can cause breast and ovarian cancers can today change the lives of some women; and someday it may bring revelations of vital importance to all women.

While breast cancer is the most common form of cancer among women (other than skin cancers that are usually curable), it's important to realize that seven out of eight women will not develop breast cancer in their lifetimes. However, those statistics are almost reversed for women who inherit certain genetic mutations. They may have an 80 percent lifetime risk of developing breast cancer and a 60 percent chance of developing ovarian cancer.

In a way, the hunt for a breast cancer gene began centuries ago. Ancient Greek literature contains descriptions of families apparently plagued by breast cancer. In the mid-19th century, the famous French physician Pierre Paul Broca (a key speech center in the brain is known as "Broca's area") documented dozens of cancer deaths over several generations of his wife's family. Though he speculated that some inherited factor might play a role, his questions came a hundred years before the scientific tools were devised that could solve such genetic riddles.

More recent studies highlighted the fact that if a woman's mother had breast cancer, she was more likely also to develop the disease. Researcher Mary-Claire King, Ph.D., now at the University of Washington, mathematically analyzed the patterns of breast cancer and found they fit the profile of a genetic disease. "It didn't prove the genetic inheritance," she says of her analyses. "It just said this is a plausible hypothesis... Then we took advantage of the revolution of molecular genetics that was all around us to actually pin down the reality of genetic predisposition."

While the work of Dr. King and her colleagues pointed the way toward a breast cancer gene, it was a team led by Mark Skolnick, Ph.D., at the University of Utah and Myriad Genetics, Inc. that announced the discovery of BRCA1 (short for BReast CAncer 1) in 1994. That report was soon followed by the identification of a second gene, BRCA2. While other genes may be found, it appears that BRCA1 and BRCA2 account for perhaps 80 percent of inherited breast cancer and an even greater proportion of inherited ovarian cancers.

Everybody is born with two copies of each gene, one from the mother and one from the father. But researchers believe some people in high-risk families are born with only one working copy of one of these critical genes; so if that single gene fails, there's no back-up, and the result can be cancer.

It's important to note that inherited breast cancers account for only 5-10 percent of the total. In other words, out of the 180-thousand cases of breast cancer diagnosed in the United States in a year, perhaps 10-thousand to 15-thousand cases may be directly linked to a genetic mutation that a woman inherited from her parents. (The mutations can be passed on by either the father or the mother. Men with a BRCA2 mutation have a 5- to 10-percent chance of developing breast cancer.) Experts refer to the vast majority of breast cancer cases as "sporadic;" that is, whatever the cause of the cancer may be, there is no evidence of a predisposition passed down in the woman's genes.

For ovarian cancer, the general lifetime risk is about 1 percent. A mutated BRCA1 gene may increase lifetime risk to between 40 and 60 percent.

The rates of inherited cancer are not the same for all women. As many as one or two out of a hundred women of Ashkenazi Jewish heritage may carry certain types of BRCA1 mutations, while the rates are much lower among other groups. Almost all of the research to date has been done in women of European heritage. Breast cancer gene risks among women of African, Asian, or Native American heritage are only now being explored.

How the genetic mutations lead to cancer is a mystery researchers are working hard to unravel. If the answers offer hints to developing new treatments, the work could benefit every woman, not only those women in families with genetic mutations.

This much is known: as with all genes, BRCA1 and BRCA2 carry coded instructions that tell cells within the body how to build certain proteins. When the genes are fatally flawed, the proteins they produce don't work properly. Though the exact nature of the errors is still being investigated, the result is that the body's system for controlling cell growth fails. Cells in the breast (with either BRCA1 or BRCA2 mutations), cells in the ovaries (in the case of a BRCA1 mutation) or sometimes other cells in the body begin multiplying without limit, piling up into tumors and spreading, or metastasizing, throughout the body.

Unfortunately for researchers trying to understand the genetics of cancer, the BRCA1 and BRCA2 genes, and the proteins they make, are very large and complicated, so there are many different ways they can fail. One study uncovered more than a hundred different and unique mutations of BRCA1 alone; some could cause cancers, others did not, but the meaning of many of the mutations was unclear.

Even before the discovery of BRCA1 and BRCA2, genetics could use family histories and genetic markers to estimate cancer risks in some families; but now genetic testing is much easier. However, the questions raised by breast and ovarian cancer gene tests are by no means easy to answer.

Who should be tested?

Experts say genetic testing for breast and ovarian cancer gene mutations would be useless and perhaps even harmful for the vast majority of women. Even the makers of a commercial gene testing service put strict limits on who will be accepted; Oncormed requires prospective patients to be adults who have been evaluated by a physician for signs of inherited cancer risk, including several relatives with cancer, cancers that occur unusually early in life, or men in the family with breast cancer. Genetic counseling is also a requirement.

Oncomed vice-president Leslie Alexandre says, "It's not like any other laboratory test. You don't just order the test and give somebody their results and away they go. Again, it has to be provided in the context of counseling and risk assessment and full knowledge about what they are doing. And it's also fairly expensive." The testing itself runs from a few hundred dollars to simply check for a specific mutation already known to exist in a certain family; to more than 2-thousand dollars for a multi-level investigation checking through a series of mutations.

What happens when testing is done?

Gene testing is almost always a family affair. In most cases, the first test is done on a family member who already has cancer, in order to identify which mutation affects that particular family. Then other members of the family who want to be tested give blood samples which are checked for the presence of the mutation. The results are also a family affair. A parent who learns she or he has a mutated gene also then knows that there is a 50-50 chance the mutation was passed along to each of her or his children.

Families are affected by the psychological repercussions of gene test results. Parents often feel guilty about passing a mutation on to their children; and a daughter may feel resentment at having inherited the mutation. Even family members who learn they do not have a mutated gene may be upset and wonder why they were spared when many of their relatives were not.

What do the results mean?

A positive test, meaning a mutation was found, means a person has a higher risk of developing cancer. A negative test, though, does not mean a person will never get cancer. There is always the "background" lifetime risk of 12 percent for breast cancer and one percent for ovarian cancer. Also, in families with an unusual amount of cancer, a mutation may exist that is currently undetectable by available tests. There are also genetic mutations unrelated to either BRCA1 or BRCA2 that can increase the risk of various cancers including breast and ovarian cancers.

Then what?

This is perhaps the most complicated question of all. Even with the same test results and family background, different people react differently to learning they are likely to develop cancer. The lack of simple or easy treatments makes the question even tougher. Genetic counselors speak of "fear management." Vickie Venne, genetic counselor at the University of Utah, says, "We have gals who are doing breast self-exams every other day, we're teaching them why that's not appropriate. We have some folks who are really very, very scared and really almost immobile sometimes, in terms of being able to go to mammography because they are so terrified that this is going to be the one that's going to show a cancer."

Venne points out that women need to understand what their current risk is, as opposed to their lifetime risk. For instance, while a woman with a mutated BRCA1 gene may have an 80 percent lifetime risk of breast cancer, if she is in her 30's she has a 20% chance of developing breast cancer within the next decade. This risk is still much higher than normal, but in most cases she won't get cancer soon.

The statistics are even more dramatic for ovarian cancer risk. "The lifetime risk of ovarian cancer in a woman with a breast cancer mutation is 65 percent. So does that mean 31-year-olds ought to go out and have their ovaries out as a prophylactic measure?," asks Venne. "No, let's look at what the risks are of ovarian cancer for someone in their 30's. It's not very high, it's virtually zero." Venne says it's reasonable then for a woman to wait until she is finished having children before having her ovaries removed. Recent research supports that strategy.

Doctors often recommend frequent mammograms and examinations in order to improve the odds of catching breast cancer early. The lack of effective screening tests for ovarian cancer means removal of the ovaries is more often considered by women at high risk. Recent studies have found that women at high risk may reduce their risk some, though not entirely, by having mastectomies even before there are any signs of cancer. As Dr. King says, "We'd like to have something else, we'd like to have something that's not nearly so invasive, that doesn't require removal of organs, but that would prevent the disease. It's very, very frustrating."

Researchers are looking to see if tamoxifen, which is being tested as a preventive treatment to fight breast cancer, has an effect in women with BRCA1 and BRCA2 mutations, but those results are not yet available.


One of the controversies surrounding genetic testing involves insurance and employment. Test results showing the presence of a genetic mutation that are put into a person's medical file may be open to employers or insurance companies. For that reason, some people keep gene test results in a separate file. People seeking individual health, life, or disability coverage, or young people seeking their first insurance coverage are the ones most likely to face questions about genetic cancer risks.

Recent health insurance legislation limited the ability of insurers to exclude people who already have insurance because of "pre-existing conditions," which might include genetic mutations, but there are no bans against increasing the cost of premiums. Several bills to protect the privacy of genetic test results are pending before Congress. In general, the insurance industry argues genetic test results should not be treated any differently than other medical information.

Life-threatening mutations of BRCA1 or BRCA2 devastate some families; but most people in the general population are not directly at risk. Nevertheless, researchers believe that by studying what goes wrong when these genes are mutated, they can someday reach a deeper understanding of what causes all sorts of breast and ovarian cancers. As Dr. King says, "It's another piece in a complex puzzle, and these are important pieces. It's going to help solve the whole thing, but that's not going to happen imminently."

For now, the discovery of breast and ovarian cancer genes offers people in certain families powerful knowledge about their futures, but frustratingly difficult choices about how to use this often stunning information.

Related Links:

National Society of Genetic Counselors - counselor listings:

American Society of Human Genetics:

Statement on Use of DNA Testing for Presymptomatic Identification of Cancer Risk by the National Advisory Council for Human Genome Research:

Promoting Safe And Effective Genetic Testing In The United States: Principles And Recommendations; NIH-DOE Working Group on Ethical, Legal, and Social Implications of Human Genome Research:  


Jill E. Stopfer, M.S.
Genetic Counselor, University of Pennsylvania Cancer Risk Evaluation Programs

Mary Claire-King, Ph.D.
University of Washington

American Cancer Society, Cancer Facts and Figures, 1997

"Tumor Variation in Families with Breast cancer," H.T. Lynch et al., Journal of the American Medical Association, v. 222, pp. 1631-35, 1972.

"Mutations and Polymorphisms in the Familial Early-onset Breast Cancer (BRCA1) gene," F.J. Couch, et al., Hum Mutat, Volume 8 (1), pp. 8-18, 1996

Statement of the American Society of Human Genetics on Genetic Testing for Breast and Ovarian Cancer Predisposition

"A Descriptive Study of BRCA1 Testing and Reactions to Disclosure of Test Results," H.T. Lynch, et al., Cancer, Vol. 79 (11), pp. 2219-2228, June 1997.

"Decision Analysis - Effects of Prophylactic Mastectomy and Oopherectomy on Life Expectancy among Women with BRCA1 and BRCA2 Mutations," D. Schrag, et al., The New England Journal of Medicine, Vol. 336 (20), May 15, 1997.

Genetic Privacy and Nondiscrimination Act of 1997 (Introduced in the House) [H.R. 341.1H]

Genetic Information Nondiscrimination in Health Insurance Act of 1997 (Introduced in the House) [S. 89.IS]

Genetic Protection in Insurance Coverage Act (Introduced in the House) [H.R. 2216.1H]

Genetic Nondiscrimination in the Workplace Act (Introduced in the House) [H.R. 2215.1H]

Oncormed, Inc. (Now part of Gene Logic)

Source: Exclusive SHN Report 

Copyright 1998 by Sapient Health Network. All rights reserved. 

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