Over the past decade, Jeff Boyd, phd, has made numerous contributions to advancing our understanding of the molecular genetics of both ovarian and endometrial cancers. In the current paper, he presents a comprehensive and thoughtful review of recent advances in the field of hereditary ovarian cancer. It is estimated that about 5% to 10% of ovarian cancers are due to autosomal-dominant hereditary syndromes. After a long period of little progress in the 1970s and 1980s, most of the genes responsible for the syndromes have been identified. Germ-line mutations in BRCA1 appear to account for the majority of hereditary ovarian cancer cases, with BRCA2 accounting for a much smaller fraction. Inherited mutations in the mismatch repair genes also cause some hereditary ovarian cancers, as may a small fraction of undiscovered genes.
Ovarian cancer is highly lethal and the cure rate is only about 30%. These cancers do not have an identifiable pre-invasive phase and produce few symptoms early in the course of disease. As a result, most patients present with diffuse metastatic disease at diagnosis. Available screening tests, such as ultrasound and CA-125, have not yet proven effective for screening and remain investigational.
Integrating Genetic Tests Into Clinical Practice
As the genetic basis of hereditary ovarian cancer comes to light, the potential exists to identify a subset of women at high risk of developing this cancer. I feel that there is good reason to believe that genetic testing can be integrated into clinical practice and can have a positive impact on both ovarian cancer incidence and mortality.
One approach to using genetic testing to decrease ovarian cancer deaths is to focus screening efforts on mutation carriers. The higher incidence of ovarian cancer in carriers would be expected to enhance the performance of screening tests and lead to a higher positive predictive value. Alternatively, prophylactic oophorectomy should prevent most ovarian cancer cases. None of the approximately 20 BRCA1-associated ovarian cancers that were treated at the Gynecologic Oncology Service at Duke University developed prior to age 40 years. Thus, prophylactic oophorectomy can probably be safely delayed to allow women to complete their families.
Once a mutation in a cancer susceptibile gene is identified in an individual, other members of the family can be rapidly and inexpensively tested. This provides us with an opportunity to reassure women in these families who have a negative test that they are probably not at increased risk of developing ovarian cancer.
Obstacles to Clinical Application
Several major obstacles to the clinical application of genetic testing exist, however. First, it now appears that the initial estimate of a 30% to 60% lifetime risk of ovarian cancer in BRCA1 carriers probably is too high. Population-based studies, now underway, will better define the frequency of germ-line mutations in cancer susceptibility genes, as well as the factors that affect their penetrance. It has been shown that pregnancy and birth control pills decrease the risk of ovarian cancer in the general population, but it is not clear that these factors are protective in mutation carriers.
Another dilemma in the clinical application of genetic testing stems from individuals found to have a mutation of uncertain significance. Although most BRCA1 and BRCA2 mutations predict truncated protein products, missense mutations that encode a full-length protein product occur in about 15% of cases. In some families it may be difficult to distinguish deleterious mutations from polymorphisms. Segregation of a missense alteration with cancer in a family suggests, but does not prove, its significance. Recently, a functional assay has been developed that involves transfection of specific mutations into yeast. This assay may aid in determining the biological significance of missense alterations.
The woman with a strong family history in whom a cancer susceptibility mutation cannot be identified also represents a difficult problem. Testing methods currently available do not detect 100% of deleterious mutations in known genes and other undiscovered ovarian cancer susceptibility genes may exist. New technologies that allow a DNA sample to be hybridized with a chip containing all possible gene mutations are under development. It is hoped that this approach will facilitate tests that are highly accurate and relatively inexpensive.
Patient Education and Counseling
Some have suggested that genetic testing should be confined to a research setting, since potential benefits remain unproven. On the other hand, it can be argued that the appropriate role of “experts” is to provide nondirective counseling and allow individuals to decide for themselves whether or not to undergo testing. Since cancer susceptibility testing is a relatively new development, however, all would agree that women should receive pretest educational materials and counseling. In addition, posttest counseling and follow-up are crucial to helping women work through various issues.
The psychological sequelae of testing may be significant regardless of whether one receives a positive or negative test result. In our experience at Duke University, it has been exceedingly helpful to have genetic counselors involved in the process. They provide expertise in this area and are able to devote more time than busy clinicians to each patient.
Confidentiality Issues
Confidentiality remains a critical issue in cancer susceptibility testing. Although it appears likely that legislation to protect against discrimination on the basis of genetic information will be enacted, there is still much uncertainty. Some individuals may ask their insurance companies to pay for testing and allow this information to be entered into their medical records. Others will continue to pursue testing privately, either through a research study or by paying themselves for commercial testing.
In this transitional period, it is difficult for physicians to decide what to document in medical records. If it is noted that a patient is at high risk of carrying a mutation and should consider genetic testing, one could be accused of failing to respect confidentiality. Conversely, vague notes designed to protect confidentiality leave one open to the accusation of having failed to adequately inform an individual of the possibility that he or she may carry a mutation in a cancer susceptibility gene. Resolution of these and other issues present significant challenges for the future.
A 48-year-old female presents with complaints of irregular vaginal bleeding and postcoital bleeding. Images from a PET/CT and pelvis MRI reveal characteristic findings. What is your diagnosis?
