Hundreds of years ago in an Ashkenazic Jewish community a DNA mutation occurred which would have an impact on thousands of Jews in the twentieth century. A Jewish baby conceived from a mutated sperm or egg became the ancestor who transmitted a faulty version of the breast cancer gene, BRCA1, to his or her children and to perhaps dozens of subsequent generations. Today many thousands of Ashkenazic Jewish women and men around the world carry that mutated gene. Most female descendants who have inherited the mutated BRCA1 have developed or will develop breast or ovarian cancer. A mutation in a second gene, BRCA2, arose in the Ashkenazic population as a result of another independent genetic event - occurring at another time and place. Women who have inherited that mutation also have greatly increased risk for breast cancer.
It is estimated that 1 out of every 50 Ashkenazic Jews carries a mutant copy of either BRCA1 or BRCA2. Although other types of mutations in BRCA1 and BRCA2 do exist in the general population, the two specific mutations associated with Ashkenazic Jews have not been found in the non-Jewish population. Most startling is that women who inherit mutant forms of BRCA1 may have up to an 85% risk of contracting breast cancer and a 44% risk of contracting ovarian cancer in their lifetimes. This compares with an overall 12% risk of breast cancer and 1% risk of ovarian cancer in the general population.
To Test or Not to Test?
The recent discovery of specific mutations in breast cancer genes which are found predominantly in Ashkenazic Jews has led to an unprecedented and devastating dilemma. Jewish families where one or more women have had breast cancer may need to consider the question of whether or not to genetically test unaffected members, and what to do about those individuals identified as carriers of a cancer gene. There are a range of reactions and a spectra of ways to deal with the presence of a faulty BRCA gene. Some women have elected prophylactic mastectomy and ovarian surgery, preferring to lose their breasts and ovaries rather than risk up to an 85% chance of breast cancer and 44 % chance of ovarian cancer. Even those drastic steps are not foolproof solutions since modern surgery still cannot remove every last cell, and some cases of breast and ovarian cancer have been reported in women who had those organs removed. Other women elect a program of careful and frequent medical monitoring, including frequent mammograms and breast self examination, and they take their chances on contracting cancer. Some women refuse to be screened and would rather not know whether they carry the gene.
What does that mean in terms of breast cancer and Jewish women? First of all, it is important to understand that most cases of breast cancer are not due to inherited cancer genes. Other factors involved include environmental factors, lifestyle, hormonal factors, or other inherited traits. That means that if you are a woman who does not have the mutant BRCA1 or BRCA2 genes you still run a high risk of breast cancer. On the other hand, inheriting a breast cancer gene does not automatically condemn a woman to contracting the disease. We inherit two copies of most of our genes, one from each parent. In many cases this acts like an insurance policy, so that when a faulty gene is inherited, a backup copy is available to perform that gene's function. Scientists believe that both copies of either BRCA1 or BRCA2 must be mutated in order for cancer to occur. This should make the event exceedingly rare since the chance of a random mutation striking both copies of the same gene is minuscule. Inheritance of both mutated genes from two parents who are carriers should also be rare. If 1 out of every 50 Ashkenazic Jewish parents has a copy of the gene, then in approximately 1 out of every 2,500 Ashkenazic couples (1/50 times 1/50) both members would carry the gene. Twenty five percent of their offspring, or 1 out of every 10,000 Ashkenazic Jewish offspring would inherit both genes.
The Transmission Process
The problem is that inheriting two mutant copies from two different parents is not the only way to get two mutant copies of a BRCA gene. If you inherit one mutant copy of the gene, and the second "backup" copy mutates on its own, then cancer will occur. Mutations can occur in our cells at any time. They are rare events but they do occur, and they happen randomly. Most mutations usually do not have a great impact on any individual adult cell; after all, we have a backup copy of most of our genes. In addition, our cells have repair enzymes which can detect and fix many of those mutations. Even if an occasional adult cell dies because of having two faulty copies of an important gene, it is likely to go unnoticed in our adult bodies where over a trillion cells perform the various functions, and there are many backup cells to compensate for malfunctioning ones. However, the BRCA genes in their normal forms are such important genes since they control cell growth and suppress cancer. When BRCA genes are not functioning properly, the cells begin to grow out of control, and cancer develops. Even though genetic mutation is rare, since there are billions of breast cells in which the mutation can occur, that mutation in the backup gene can occur at random in a cell; and all it takes is one cancer cell dividing out of control to form a breast tumor. If a woman already has one faulty copy of a BRCA gene, a mutation in the backup copy will have a dramatic and possibly fatal impact on her life.
The Screening Dilemma
Genes for Tay Sachs and certain other inherited diseases are prevalent in Jewish populations and Jewish couples have been grappling with decisions regarding screening of fetuses, abortion, and related dilemmas. Those dilemmas are devastating to the families who deal with them and are tragic for them and for the afflicted children. However, those genetic diseases are rare compared to breast cancer. In the general population, a woman who lives to the age of 80 has a one in nine chance of contracting breast cancer, so this disease affects a very large proportion of the population (especially if you consider the impact on each victim and her family) . A significant dilemma which exists in regard to the BRCA genes is that the decisions to be made are not clear cut. Inheriting either of the mutant BRCA genes may increase the likelihood of contracting cancer significantly, but not to 100%. So women must grapple with whether to undergo major surgery, or to watch and wait.
Most medical practitioners do not recommend universal testing of all Ashkenazic Jewish women for the BRCA genes. Doctors are concerned that negative tests will result in complacency when there should still be vigilance. After all, most cases of breast cancer are not due to inheritance of cancer genes. When there is clear evidence of a genetic link to breast cancer within the family, testing for mutant BRCA1 and BRCA2 genes may be recommended. However, some people are concerned that positive test results can lead to genetic discrimination by insurance companies or employers. There is concern that women who test positive for BRCA1 or BRCA2 mutations may become uninsurable because of a previously existing medical condition.
Results of genetic testing can have great value if presented along with appropriate genetic counseling. Negative test results have helped women avoid unnecessary surgery. Positive test results have helped women make informed decisions on what steps they can take to increase their chances of a long and healthy life.
There is no easy solution to this devastating dilemma. We must learn more about the genes involved and the inheritance and action of those genes. We also need to understand how mutations occur, and how the environment can influence the rate of mutations. Many states have passed legislation to protect patients from genetic discrimination. That type of legislation must be universal, and should be continually reworked and strengthened to guarantee that we cannot be classified as uninsurable because of genetic defects. We must not be forced to be secretive about or ashamed of our genes. After all, no one is genetically perfect.
There is hope that eventually we will not only understand breast cancer and be able to predict who will get it, but also cure it. The cure for this disease should not require surgical, chemotherapeutic or radiology based treatment, but it will be a true cure based on the correction of the very genes which caused all the problems in the first place.
Sources: JCN, reprinted by permission of the author.
Dr. Miryam Z. Wahrman received her Ph.D. in Biochemistry from Cornell University Medical College and performed research at Sloan-Kettering Institute on the genetic basis of cancer.