The study of clinical syndromes that include an increased incidence of breast cancer has provided insight into the mechanisms by which genetic mutations result in the development of breast cancer. The most frequently identified pedigrees contain site-specific breast cancer (i.e., breast cancer in these families is not found in association with inherited susceptibility to other cancers, such as ovarian)and are thought to represent the effect of a single genetic abnormality. BRCA1 and BRCA2 are examples, and others are likely to be identified in the future. Breast cancer also has been noted to occur in association with other cancers.

The occurrence of breast cancer in association with diverse childhood neoplasms in the Li-Fraumeni/SBLA (s oft tissue and bony sarcomas, b rain tumors, l eukemias, and a drenocortical carcinomas) syndrome and the association between breast and ovarian cancer represent some of the most intensively studied examples. Finally, an increased frequency of breast cancer may occur in patients with hereditary syndromes that include nonmalignant manifestations as well, such as Cowden disease and Muir-Torre syndrome.

BRCA1
In 1990, chromosome 17q21 was identified as the location of a susceptibility gene for early-onset breast cancer, now termed BRCA1. Shortly thereafter, linkage between the genetic marker D17S74 on 17q21 and the appearance of ovarian cancer in several large kindreds was also demonstrated. Initial estimates suggested that BRCA1 mutations were responsible for more than 90% of breast cancer cases in families with apparent autosomal dominant transmission of breast cancer and at least one case of ovarian cancer, and 45% of cases in families with breast cancer only. However, the percentage of site-specific breast cancer cases attributed to BRCA1 mutations rose to almost 70% if the median age of onset of breast cancer in the families was younger than 45 years.

Using direct mutation testing, several groups have attempted to refine the estimates of mutation prevalence and breast cancer penetrance in BRCA1 carriers found in less striking families. In families identified through clinics treating high-risk breast cancer, BRCA1 mutations appear to be responsible for 20% to 30% of breast cancer cases and 10% to 20% of ovarian cancer cases. Estimates of BRCA1 prevalence in unselected breast cancer patients are not well documented, although initial studies suggest that the proportion is in the range of 3% as defined by two different studies.

Population Genetics of BRCA1 and BRCA2
The population genetics of BRCA1 and BRCA2 reflect several basic human evolutionary principles. It is postulated that each gene has undergone multiple mutations, and that these mutations have migrated with the people in which they occur. Certain “founder mutations” are now known to exist in BRCA1 and BRCA2. These are ancient mutations that have occurred in specific ethnic populations many generations in the past. They are thought to persist because the development of disease normally occurs after childbearing age, so that individuals carrying these mutations are able to pass them on to subsequent generations with little impact of the mutated alleles on survival of the species.

Founder mutations so far have been identified in at least nine separate ethnic subpopulations, including those in Iceland, Finland, Hungary, Russia, France, Holland and Belgium, Israel, Sweden and Denmark, and Norway. A comprehensive review of these studies by Szabo and King reveals the similarities and differences in mutation rate, penetrance, and nature of the mutations among various population groups. The proportion of high-risk families with breast or ovarian cancer appears to vary widely by population group; mutations in BRCA1 are most common in Russia (79% of families with breast/ovarian cancer), followed by Israel (47% of families) and Italy (29%).

Moreover, the population dynamics of the groups are very different; only a small number of different mutations are seen in the Russian and Israeli populations, whereas a large number of unique mutations are found in the Italian population. Thus, the number of families affected does not accurately reflect the number of different mutations present. BRCA2 mutations appear to be more common than BRCA1 mutations only in Iceland, where a single mutation accounts for virtually all of the BRCA2-associated breast and ovarian cancer.

The BRCA1 and BRCA2 mutations among the Ashkenazi Jewish population have been studied most intensively. The two most common mutations in BRCA1 are 185delAG and 5382insC, each accounting for approximately 10% of the total. These two mutations, along with a mutation in BRCA2, 6174delT, have been identified with the highest frequency in the Ashkenazi Jewish population.

The mutations 185delAG and 5382insC have been shown to occur in individuals of Ashkenazi descent with a combined frequency of approximately 1%; the estimated frequency of BRCA1 mutations in an unselected white population is less than 0.1%. This observation has subsequently been expanded to include the Moroccan, Iraqi, and Yemenite Jewish populations. Analysis of germ-line BRCA1 mutations in several cohorts of Jewish women suggests that just over 20% of Jewish women developing breast cancer before age 40 carry the 185delAG mutation. Even more strikingly, estimates suggest that 30% to 60% of all Ashkenazi Jewish women with ovarian cancer carry either a common BRCA1 or BRCA2 germ-line mutation. Other BRCA1 mutations have also been detected in the Jewish population but at much lower levels.