Characteristics of Hereditary Breast Cancer

Several clinical characteristics may distinguish an inherited form of breast cancer. In general, these include an age of onset which is 10 to 20 years earlier than the average age of onset, bilateral breast cancer, an increased occurrence of a second breast cancer, male breast cancer, the occurrence of additional cancer diagnoses in a single individual or among close relatives, the occurrence of characteristic co-morbiditites which are associated with known genetic syndromes, and the occurrence of multiple affected family members from one lineage, maternal or paternal.

Most of these characteristics may be explained by Knudson’s two-hit model of carcinogenesis (figure 2).

Knudson's 2-hit Model of Carcinogenesis Sporadic Normal Chromosome Inactivation of one allele Inactivation of both alleles NORMAL CELL CELL PREDISPOSED TO CANCER Hereditary     Inactivation of one allele Inactivation of both alleles

This model suggests that cancer develops through loss of function of both the maternal and paternal alleles (copies) of a cancer susceptibility gene. In inherited forms of cancer, there is a loss of either the maternal or paternal allele within the egg or sperm from which an individual is conceived, thus every daughter cell thereafter has 'one hit' at this genetic locus. The loss of the remaining allele (loss of heterozygosity), or 'second hit', may occur in time as the result of an environmental trigger or by chance during DNA replication. Sporadic cancers begin with two normal copies of a cancer susceptibility gene. Two successive acquired mutational events ('two hits') occurring in a single cell at each allele of a cancer susceptibility gene are necessary for the development of cancer. This process requires more time and generally occurs only once in a single cell. Thus, the distintions of an inherited form of cancer are earlier age of onset, greater chance of a second primary cancer, and cancer developinbg in several tissue types. The distribution of tissues types at risk for cancer development may depend upon the gene involved and the function of its protein product. This model of carcinogenesis may apply for tumor suppressor genes and DNA repair genes.

BRCA1 and BRCA2

Hereditary site-specific breast cancer and breast-ovary syndrome account for the majority of hereditary forms of breast cancer. As described above, BRCA1 and BRCA2 contribute to most of the genetic susceptibility in these syndromes (Figure 3).

BRCA 1

BRCA 2

Both genes are extrememly large and complex. BRCA1 is 5,592 kb in length with 24 exons, and BRCA2 is almost twice as long with 10,254 kb and 27 exons. Hundreds of mutations have been found in both genes and almost half of the mutations identified are private mutations found in only a single family (13). Most of the mutations result in a truncated protein product, thus the deleterious nature of these mutations is easily interpreted. Because the function of these genes is largely unknown, the clinical significance of missense mutations is unknown. Mutations anywhere along either gene are associated with an increased risk for breast cancer. There is some suggestion that mutations in the 5' end of BRCA1 and mutations in exon 11 of BRCA2 are more often associated with ovarian cancer, however, such genotype-phenotype correlations are not clear-cut. Identification of mutations is best accomplished by sequencing of the entire coding region and the intron-exon splice sites of these genes, where the majority of mutations are found.

The linkage studies which first identified these genes predicted that BRCA1 contributed to approximately 45% of site-specific breast cancer, and BRCA2 contributed to an additional 35%. For breast-ovary syndrome, BRCA1 contributed the susceptibility in almost 90% of families, whereas BRCA2 contributed only 5% (10). These pervalence rates may be overestimates due to the potential bias introduced as a result of the ascertainment scheme which was intentionally employed for the study of these very high risk families. A recent clinic-based estimate of BRCA1 mutation prevalence suggested that BRCA1 mutations among families with an average of 3 to 4 affected members is much less at 16% (14). However, the likelihood of identifying a BRCA1 mutation did increase with an earlier age of breast cancer onset and the presence of ovarian cancer (Table E).

Population-based estimates of the prevalence of BRCA1 and BRCA2 have been derived from segregation analyses, germline mutation analysis of unselected breast and ovarian cancer cases, and germline mutation analysis of breast and ovarian tumors (Table F). Segregation analyses suggest that 4.2% of all breast cancers and 5.3% of all ovarian cancers occurring by age 70 are due to mutations in BRCA1 and BRCA2 (15). Germline mutation analyses in women with breast cancer occurring before age 35 have found that approximately 10% had BRCA1 mutations (16). In a series of unselected ovarian cancer patients, the prevalence of germline BRCA1 mutations was estiamted to be 5% (17). Germline BRCA2 mutations were found in 3% of consecutive epithelial ovarian tumors (18).

In the United States, common mutations in BRCA1 and BRCA2 are found in the Ashkenazi Jewish population. In BRCA1 there are two common mutations, 185delAG and 5382insC. In BRCA2 a third common mutation exists, 6174delT. In a study of anonymous blood samples which were initially provided for Tay-Sachs screening, the 185delAG was found in approximately 1% of individuals, the 5382insC in 0.1%, and the 6174delT in 1.5% (19,20). A study investigating these common mutations among Jewish families with two or more cases of breast cancer found the prevalence was 29%, and in families with two or more cases of breast cancer and at least one ovarian cancer the prevalence of these mutations was 73% (Table G) (21).

The likelihood for cancer development due to mutations in BRCA1 and BRCA2 (penetrance estimates) have also been derived from the above mentioned segregation studies and linkage analyses, as well as the from a recently published population-based study of the common Jewish mutations (Figures 4 and 5). Segregation analyses of breast cancer and ovarian cancer have estimated that the penetrance of BRCA mutations for these cancers by age 70 is approximately 75% and 20%, respectively (9,15). Linkage studies have provided greater penetrance estimates for breast and ovarian cancer (22). By age 70, the risk for breast cancer is estimated to be 85% the risk for ovarian cancer is estiamted to be 40 to 60. In addition to these cancers, colon cancer and prostate cancer risk was increased 3 and 4 fold, respectively. Population-based mutation analyses of the three common Ashkenzai mutations (23) are closer to the segregation analyses estimates, with a 56% likelihood of breast cancer development and a 16% likelihood of ovarian cancer development by age 70. In this study an increased colon cancer risk was not apparent, however, prostate cancer risk was 16% by age 70 versus a population risk of 4%. There were no geneotype-phenotype correlations noted as each of the three common Jewish mutations conferred similar cancer risks.