Hereditary Breast Cancer Syndromes

Other Types of Cancers Associated with Mutations in BRCA1
Risk for cancers other than breast and ovarian cancer also appears to be increased in the presence of an inherited BRCA1 mutation. The first such indication came from the study of a large Icelandic family group with breast and ovarian cancer, which suggested that prostate cancer also is a component of the BRCA1 syndrome. Subsequently, the Breast Cancer Linkage Consortium estimated a relative risk of 3.33 for prostate cancer and a relative risk of 4.11 for colon cancer in males thought to carry BRCA1 germ-line mutations.

However, the excess colon cancer risk in this study reflects the experience of only a few families, which suggests either very low penetrance with regard to colon cancer or a limited number of specific mutations that increase colon cancer risk. No significant excesses were observed for cancers originating from other anatomic sites, and male breast cancer is only rarely associated with BRCA1 germ-line mutations.

Pathobiology of BRCA1-Associated Breast Tumors
The relationship between BRCA1 and tumor prognosis is one of the key clinical questions that followed the identification of BRCA1. In the first study to address this question, Lynch et al. analyzed 180 tumors from families with hereditary breast/ovarian or site-specific breast cancer. Ninety-eight of the 180 tumors they studied were classified as the “BRCA1 group.” These tumors were thought to have the highest likelihood of arising as a result of BRCA1 mutations but were not directly tested for mutations.

The BRCA1 group was found to include more aneuploid and more high S-phase tumors; however, surprisingly, disease-free survival was longer for patients whose tumors were of this type than for those whose tumors were thought less likely to have BRCA1 mutations. Subsequent studies have verified that BRCA1-associated tumors are often high grade and tend to be estrogen-receptor and progesterone-receptor negative. Genetic studies of BRCA1-related breast and ovarian tumors further indicate that these tumors are both genetically unstable and highly proliferative.

Whether the aggressive pathologic features described in association with BRCA1-associated breast tumors translate into reduced survival or lack of response to standard treatment strategies is not yet clear, but data are accumulating that these high-grade lesions behave as would be expected. In addition, a study of Ashkenazi Jewish BRCA1 mutation carriers suggested that a BRCA1 mutation is an adverse prognostic factor in its own right. Ongoing large-scale studies are currently under way to address this issue in mutation carriers, in the context of other known prognostic factors.

BRCA1 Gene Structure and Mutation Spectrum
The BRCA1 gene is composed of 24 exons, or coding regions, and is translated into a protein consisting of 1,863 amino acids. This is important from a clinical standpoint in the context of genetic testing, because this very large size makes screening the entire gene for mutations technically demanding and costly. The entire gene covers approximately 100 kb of genomic sequence, and in the case of BRCA1, this region contains a large number of repetitive elements called Alu repeats.

Of clinical importance, these repetitive elements facilitate the generation of large deletions and duplications in BRCA1, creating disease-associated mutations that are not detectable by methods in current use in commercial testing laboratories. The prevalence of these mutations in the United States is not known yet, but three such mutations account for 36% of BRCA1 mutations in the Netherlands. These mutations clearly represent a potential source of a significant number of false-negative BRCA1 tests.

Now that BRCA1 has been identified, more than 500 coding region sequence variations have been detected. A listing and description of most known BRCA1 mutations is available on the Breast Cancer Information Core (BIC) website. Surprisingly, almost all described mutations are found in the germ line. Somatic BRCA1 mutations are rare in sporadic breast and ovarian tumors, a finding which suggests that BRCA1 coding region mutations play a limited role in the development of sporadic breast cancer. Whereas only one report of an individual with two BRCA1 mutations exists in the literature, a number of individuals who carry both BRCA1 and BRCA2 mutations have been described.

Preliminary work has begun to identify possible correlations between specific BRCA1 mutations and the types of cancers that subsequently develop. Two studies have suggested that mutations in the 5’ half of BRCA1 predispose to both breast and ovarian cancer, whereas mutations closer to the 3’ portion of the gene are predominantly associated with site-specific breast cancer.

This correlation has been observed in several European studies but is rarely seen in the BRCA1 population in the United States. It appears to be due largely to the reduced penetrance of ovarian cancer associated with these mutations rather than to an increased incidence of breast cancer arising in association with mutations in the 5’ end of the gene. Finally, mutations occurring at either end of BRCA1 may be associated with a more severe phenotype, as defined by high tumor grade, suggesting that these two regions may be important for the control of mammary cell growth. Identification of these specific genotype/phenotype correlations will ultimately aid clinicians in recommending appropriate screening, prevention, and treatment strategies in women with known BRCA1 mutations, but at present these data are too preliminary to be used in counseling women with known mutations.

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