Clinical Considerations in the Management of Individuals at Risk for Hereditary Breast and Ovarian Cancer

Mark E. Robson, MD


Cancer Control. 2002;9(6) 

In This Article

Prevalence of BRCA1 and BRCA2 Mutations

Several series have examined the prevalence of germline BRCA mutations in population-or hospital-based samples of breast cancer patients. These studies are all likely to underestimate the true prevalence of such mutations, as current testing methodologies are incompletely sensitive. Bearing this limitation in mind, studies have demonstrated BRCA1 mutations in 3.5% to 6.2% of women with early-onset breast cancer and BRCA2 mutations in 2.1% to 3.4%.[12,13,14,15] These studies have been conducted in populations of mainly European ancestry, and the prevalence of mutations in other groups has not been established. The available studies indicate that BRCA1 mutations can be identified in approximately 4% to 5% of ovarian cancer patients and BRCA2 mutations in 1% to 2%.[16,17,18]

Although BRCA mutations are relatively uncommon in women with breast or ovarian cancer, they may be observed with greater frequency in affected women who also have family histories of these diseases. A number of familial cancer risk assessment clinics around the world have identified mutations in either BRCA1 or BRCA2 in 21% to 73% of individuals undergoing testing.[19] The ascertainments in these reports are extremely varied, including families from differing ethnic backgrounds with greater or lesser numbers of affected relatives at varying ages. As noted above, in the families whose pedigrees are most suggestive of a hereditary predisposition, such as those included in the BCLC, the probability that a predisposition may be linked to BRCA1 or BRCA2 may be as high as 87%. Lower average age at onset, bilateral breast cancer, ovarian cancer, or male breast cancer within the pedigree all increase the probability that the observed family history is the result of a BRCA mutation. General guidelines for family histories that are suggestive of a prior probability of detecting a BRCA mutation of 10% or greater, based on a reference laboratory experience testing 10,000 individuals, are outlined in Table 2 .[20] These estimates are not applicable to populations in which specific founder mutations are segregating. The probability of detecting a familial mutation is always greater when an affected woman is tested, but certain family structures may be sufficiently suggestive to warrant the offer of testing to unaffected individuals if no suitable living affected individual is available. In this circumstance, however, caution must be taken in the interpretation of a "negative" result. It is well established that currently available technology cannot identify mutations in all families whose histories are strongly suggestive of a BRCA-related predisposition. Specific mutations were detected in only 64% of the BRCA1-linked families in the BCLC who underwent direct mutation analysis, although this analysis was occasionally incomplete. A recent collaborative study of a test set of blinded samples containing 58 distinct BRCA1 mutations demonstrated sensitivities of 60% to 91% with several different mutation analysis methodologies.[21] As a result of this limited analytic sensitivity, it is critical that individuals in whom BRCA mutations are not detected remain aware of the possibility of hereditary risk and continue to perform surveillance as indicated by their family history. The exception to this injunction is in the situation where a deleterious mutation has already been identified in another family member. In this circumstance, individuals who do not carry the familial mutation are usually considered to have the same cancer risk as the general population, unless pedigree analysis suggests the possibility of a genetic predisposition transmitting from the other lineage than the one with the known mutation.

Individuals from certain ethnic groups may be more likely than members of the general population to carry specific BRCA mutations. Shortly after the identification of BRCA1 and BRCA2, two specific BRCA1 alterations (185delAG, also known as 187delAG, and 5382insC) and one BRCA2 mutation (6174delT) were shown to be carried by approximately 1 in 40 individuals of Ashkenazi (Central and Eastern European Jewish) descent.[22,23,24,25] One of these mutations may be identified in approximately 10% of unselected Ashkenazi women with breast cancer and in up to 30% to 40% of women with either early-onset breast cancer or ovarian cancer.[26,27,28,29] It is important to note that mutations other than the common founder alterations have been observed in Ashkenazi families,[20,30,31] and thus Ashkenazi families with "negative" testing for the founder alleles cannot be reassured that they lack a detectable predisposition. It is also important to note that the Ashkenazim are not the only ethnic group in which BRCA founder mutations have been identified. Similar alterations have been noted in other groups, such as the Dutch and the population of Iceland.[32,33] Although less well studied than the Ashkenazim, the contributions of these mutations to familial cancer in their respective populations may be significant.


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