BRCA1 Mutations and Breast Cancer Screening
BRCA1 Mutations and Breast Cancer Screening
ABSTRACTS & COMMENTARY
Synopsis: Genetic testing for BRCA1 mutations has become commercially available and increasingly requested in the community. Reports of certain high-risk populations indicate a significant association of such mutations with breast (and ovarian) cancer predisposition. Two recent reports indicate that, within the general community, and even in those with a presumed predisposition (early onset disease, or those with a strong family history), the numbers of individuals with positively identified mutations is quite small. The reports raise serious concerns about the widespread use of analysis of this gene.
Sources: Newman B, et al. JAMA 1998;279:915-921; Malone KE, et al. JAMA 1998;279:922-929; Couch FJ, Hartmann LC. (editorial) JAMA 1998;279: 955-957.
Since the identification and cloning of the BRCA1 gene,1 there has been great anticipation that screening for observable mutations might prove useful in determining a woman's risk for breast cancer. Indeed, in earlier studies in highly selected populations, abnormalities of this gene were found in a high percentage of women with apparent family predisposition to breast or ovarian cancer.2-4 However, the actual prevalence of BRCA1 gene mutations in the general population, or even in those with early-onset breast cancer, has not been clearly established. Establishing such population-derived information is important because there is now a widespread appreciation within the general community of the commercial availability of genetic testing for risk assessment. Yet, investigators in the field have not developed a consensus on the value of widespread application of this cumbersome and expensive testing. The problem is not made easier by the BRCA1 gene itself. It is large and complex: 24 exons, 5592 nucleotides, and already more than 130 germline mutations in the coding region identified.5 Mutations that result in frame-shift or missense errors that result in truncated, dysfunctional proteins seem to be related to disease predisposition, whereas a large number of less deleterious mutations have been described and their biological and clinical relevance are yet to be determined. In addition, the degree of allelic variation has not been defined.
Two recent papers and an editorial published in JAMA provide useful information for helping establish appropriate recommendations for who should be screened. Newman and associates, using a case-control study design examined lymphocytes from 211 patients with breast cancer (aged 20-74) and 188 age-matched controls (all races), and, subsequently, 99 additional patients with breast cancer (and 108 controls) of African-American heritage. They found only three cases in which there were known disease-related mutations in the first 211 patients, and none in the African-American patients. Five patients had missense mutations of undetermined importance. The presence of the disease-related mutations was not influenced by age at diagnosis. However, among those with a family history of ovarian cancer or a strong family history of breast cancer (four relatives including the proband) the risk for BRCA1 mutation was higher (23% and 13% respectively).
Malone and colleagues, also using case-control methodology and peripheral blood lymphocyte genetic analysis, examined two sets of individuals perceived to be at high risk for BRCA1 mutations. Women younger than 35 at the time of diagnosis (with or without family history) (n = 193) and women younger than 45 at time of diagnosis with a primary family history (n = 208) were included. In those younger than 35 years old, 12 (6.2%) had germline mutations while for those younger than 45 with a positive family history, 15 (7.5%) had germline mutations. No disease-associated mutations were observed in the controls (aged 21-44 years; n = 71) with a first-degree family history or in the randomly selected controls (aged 40-44 years; n = 199). Within both groups of patients, mutation frequency decreased with advancing age and higher proportions of mutations were seen in patients with at least one relative diagnosed as having breast cancer before age 45. Also, there was a greater risk for BRCA1 mutation in cases with greater numbers of affected relatives and in those with a family history of ovarian cancer.
COMMENTARY
What is the take-home message from these two reports? First, it is telling that, despite all of the statistical evaluation and subgroup analysis, of the 310 patients (in the two different cohorts) and the 296 controls reported from the North Carolina study (Newman et al), only three patients and no controls were found with relevant disease-associated frame-shift or missense mutations. This was a general population study, not a group selected for high risk of genetic predisposition, but the data did seem to indicate that under certain conditions (those with a strong family history of breast or ovarian cancer), the likelihood of BRCA1 mutation is higher. It is also important to note that none of the African American patients or controls had disease-associated mutations, although missense mutations of undetermined significance were noted in a few. In the Washington study (Malone et al), the populations were selected because of the suspicion of genetic predisposition in women with early-onset breast cancer or in pre-menopausal women with a family history of breast cancer. Again, the numbers of BRCA1 mutations were small, but greater than the general population noted above. The great majority of young women with breast cancer, with or without a family history, were free of BRCA1 mutations. The data raise significant doubts about the value of widespread screening for those concerned about predisposition to breast cancer. It is apparent that those with early-onset breast cancer or those persons with a strong family history of breast or ovarian cancer are at higher risk for mutation. However, for individuals without breast cancer (but with a similar high-risk family history), current genetic analysis is likely to be a low-yield procedure. This may be because the current technology does not reveal all of the BRCA1 mutations that are relevant to breast cancer predisposition or that other, yet to be discovered genes are also important in the pathogenesis of this disease. Both of these are likely.
Furthermore, there is another feature of genetic screening about which we currently have incomplete information. For those without apparent breast cancer but with BRCA1 mutations, what is the appropriate management? Genetic screening for disease predisposition is a popular notion that, no doubt, will be a feature of clinical medicine of the next decade and beyond. However, at this point, with regard to BRCA1 mutations and breast cancer, the data are incomplete and, despite the commercial availability, use should still be considered investigational.
References
1. Hall JM et al. Science 1990;250:1684-1689.
2. Szabo CI, et al. Am J Human Genet 1997;60: 1013-1020.
3. FitzGerald MG, et al. N Engl J Med 1996;334:143-149.
4. Levy-Lahad E, et al. Am J Human Genet 1997;60: 1059-1067.
5. Miki Y, et al. Science 1994;266:66-71.
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