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Molecular Genetics of Hereditary Ovarian Cancer

Molecular Genetics of Hereditary Ovarian Cancer

Over the last decade, there has been a virtual explosion of scientific knowledge regarding the underlying genetic basis of many human malignancies, particularly breast and ovarian cancer. The author has done an exemplary job of presenting an up-to-date review of the role of BRCA1, BRCA2, and the mismatch repair genes in the development of hereditary ovarian cancer. Clearly, this was not an easy task, as progress in this field over the past several years has been phenomenal.

A susceptibility gene for hereditary breast cancer was initially localized to the long arm of chromosome 17 in 1990. Linkage data indicated that approximately 45% of hereditary breast cancer cases and the majority of hereditary ovarian cancers were linked to a gene in this region, referred to as BRCA1. Over the next 4 years, an intense international competition ensued, culminating in the identification of the BRCA1 gene in 1994. Shortly thereafter, in 1995, a second breast cancer gene, BRCA2, was identified on chromosome 13q.

At about the same time, a novel group of genes known as mismatch repair genes were found to be responsible for disease in families with hereditary nonpolyposis colorectal cancer (HNPCC). In the few short years since that discovery, genetic testing for mutations in these genes has rapidly entered the clinical arena.

In families with hereditary breast-ovarian cancer, disease is transmitted as an autosomal-dominant trait with a high degree of penetrance. Children of an affected individual have a 50:50 chance of inheriting the disease gene and a nearly 50% risk of developing breast or ovarian cancer by age 85. Rather than basing estimates of risk on family history alone, it is now possible to determine which gene is responsible for disease in the family and to identify those children who actually inherited the disease-causing mutation and those who did not. Those who test negative can then be counseled that their cancer risk is similar to that of the general population. Conversely, those who have inherited a mutation can be advised that they have a 95% lifetime risk for developing breast cancer and a 40% lifetime risk for ovarian cancer. These mutation carriers can then be offered increased surveillance and prevention strategies.

Can Risk Be Accurately Determined?

The current review by Dr. Boyd touches on a number of uncertainties that make testing for these disease-causing genes problematic. First, can we accurately assign risk in mutation carriers? The original estimates of cancer risk in BRCA1 and BRCA2 carriers were based on data from the very large, multicase families used in the original linkage studies. In these families, the lifetime risk estimate for ovarian cancer was approximately 60% in BRCA1 carriers. However, as the author points out, more recent studies of carriers of specific mutations in Ashkenazi Jewish women unselected for family history reveal that the lifetime ovarian cancer risk for carriers of the 185delAG and 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 is closer to 16%, well below previous estimates based on high-risk families.[1] The lower cancer incidence observed in Ashkenazi Jewish women may represent allelic heterogeneity in the expression of these genes, with different mutations conferring different cancer risks.

In addition, pedigree analysis of large multicase families supports the theory of genetic heterogeneity, with some BRCA1 families containing multiple cases of both breast and ovarian cancer while in others, the excess cancer cases are strictly breast or ovarian. Several studies have suggested that mutations in the 5¢ half of BRCA1 predispose to both breast and ovarian cancer, whereas mutations close to the 3¢ end of the gene are associated with breast cancer only.[2] Such differences in gene penetrance would be important in counseling gene carriers, particularly those considering prophylactic oophorectomy.

Do Traditional Risk Factors Alter Gene Expression?

Another area of uncertainty is whether traditional risk factors alter the expression of these highly penetrant genes. Very little is known about the influence of traditional reproductive and environmental risk factors, such as diet, in BRCA1 and BRCA2 carriers. For example, recent data from a study of 331 BRCA1 mutation carriers indicates that, in BRCA1 carriers, the risk of breast cancer decreases somewhat with at least one full-term pregnancy (relative risk, 0.85) but ovarian cancer risk actually increases with increasing parity (relative risk, 1.4).[3] This increase in ovarian cancer risk with increasing parity is the opposite of what is seen in studies of the general population, and suggests that oral contraceptive use, which has been proposed as a possible preventive tool, may not decrease ovarian cancer risk in mutation carriers.

Although current screening recommendations for BRCA1 carriers include annual pelvic examination, transvaginal sonography, and serum CA-125 determinations, the effectiveness of these methods is unproven. For this reason, prophylactic oophorectomy at the completion of childbearing or at the time of menopause is recommended by the American College of Obstetrics and Gynecology.

However, as with prophylactic mastectomy, prophylactic oophorectomy is not completely protective. The occurrence of peritoneal carcinomatosis, clinically and histologically indistinguishable from ovarian cancer, has been reported in as many as 2% to 25% of high-risk women. Whether this results from metastasis unrecognized at prophylactic surgery or the later development of cancer arising from residual ovarian tissue or the peritoneum is unknown.

Implications of a Negative Test

Another concern with genetic testing relates to the implications of a negative test. Although the vast majority of BRCA1 mutations occur in the coding region of the gene, it should not be forgotten that mutations in the noncoding portions of the gene cannot be detected by current commercial tests. Although rare, these regulatory mutations can lead to false-negative results. In addition, a small proportion of inherited breast cancer cases are due to mutations in other genes, including TP53, MSH2, and MLH1.

Likewise, not all inherited ovarian cancer cases are due to BRCA1 and BRCA2 mutations. Approximately 10% occur as part of the HNPCC syndrome (hMSH2, hMLH1, and hPMS2), and evidence suggests that there are additional, yet to be identified breast and ovarian cancer genes. Also, genetic testing has failed to find mutations in families predicted to contain mutations based on prior probabilities, suggesting that we are missing mutations or that previous estimates of the proportion of families with BRCA1 and BRCA2 mutations may be inflated.

Further Study Needed

Finally, although little is known about the function of the BRCA1 gene itself, wild-type BRCA1 has been shown to inhibit the growth of sporadic breast and ovarian cancer cell lines in vitro and in nude mice.[4] These studies provide direct evidence that BRCA1 functions as a tumor-suppressor gene and that this effect is not limited to hereditary disease, suggesting that it may be useful in the treatment of sporadic disease. In fact, delivery of wild-type BRCA1 using a retroviral vector has been shown to suppress tumor growth in nude mice, and gene therapy trials in ovarian cancer patients are underway.

Clearly, genetic epidemiologic studies are needed to determine those factors that influence the penetrance of these genes, as well as the effectiveness of surveillance and prevention strategies, in mutation carriers. However, elucidation of the underlying molecular basis of disease in mutation carriers is equally important, as this knowledge should lead to novel prevention and treatment strategies for both the inherited and sporadic forms of ovarian cancer.

References

1. Struewing JP, Hartge P, Wacholder S, et al: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336:1401-1408, 1997.

2. Gayther SA, Warren W, Mazoyer S, et al: Germline mutations of the BRCA1 gene in breast/ovarian cancer families provide evidence for a genotype/phenotype correlation. Nat Genet 10:208, 1995.

3. Narod SA, Goldgar D, Cannon-Albright L, et al: Risk modifiers in carriers of BRCA1 mutations. Int J Cancer 64:394-398, 1995.

4. Holt JT, Thompson ME, Szabo C, et al: Growth retardation and tumour inhibition by BRCA1. Nat Genet 12:298, 1996.

 
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