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

Genetic Etiology of Hereditary Breast Cancer

Although an autosomal dominant predisposition to breast cancer was suspected for many years, formal demonstration of its existence was not provided until the segregation analysis of Newman et al[3] in 1988. Subsequently, Hall and colleagues[4] demonstrated that one associated locus was linked to chromosomal region 17q21, and the term BRCA1 was coined to describe the putative gene. Other investigators demonstrated that the same region was linked to hereditary ovarian cancer, confirming the previous clinical observations of ovarian cancer in families with an apparent breast cancer predisposition. After an intense multinational effort, the BRCA1 gene was isolated in October 1994, and germline mutations were detected in members of hereditary breast and breast-ovarian cancer families.[5] However, a number of families could not be attributed to BRCA1 by either linkage or direct mutation analysis. Further study of these kindreds demonstrated a second susceptibility locus, called BRCA2, on chromosome 13q12,[6] and in December 1995 the gene was isolated and shown to be mutated in some, but not all, non-BRCA1 families.[7] Linkage analysis of the hereditary breast and breast-ovarian cancer families participating in the Breast Cancer Linkage Consortium (BCLC), all of which had at least four cases of breast cancer either in women before age 60 years or in men, with or without cases of ovarian cancer, indicated that 87% of such families could be genetically linked to either BRCA1 or BRCA2.[8] Families with both breast and ovarian cancer were more likely to be attributable to BRCA1. Families with male breast cancer were more likely to be linked to BRCA2, although a significant minority were linked to BRCA1 (Table 1). Although the predisposition in most families was attributable to either BRCA1 or BRCA2, even in this highly selected group of families, a substantial proportion of kindreds with female breast cancer, but no male breast cancer or ovarian cancer, could not be linked to the known genes. Mutations in a number of genes other than BRCA1 or BRCA2 are known to predispose to breast cancer, including p53 (Li-Fraumeni syndrome), PTEN (Cowden's disease), STK11 (Peutz-Jeghers syndrome), and possibly ATM and CHK2. To date, however, alterations in these genes do not appear to explain most families with an apparent isolated predisposition to female breast cancer.

Although considerable progress has been made since the discovery of BRCA1 and BRCA2,[9] the functions of the gene products remain incompletely defined. Although these proteins appear to have multiple functions, attention has been focused on their role in DNA damage repair. Recent experiments have demonstrated that both BRCA1 and BRCA2 may be critical to a process known as homology-directed DNA repair, a specific cellular mechanism for the resolution of double-stranded DNA breaks.[10,11] Cells lacking normal BRCA1 or BRCA2 function may therefore be predisposed to acquire somatic mutations, accelerating the process of cancer development. The susceptibility conferred by a germline mutation has been thought to follow a classic tumor suppressor model, in that the normal copy of the gene appears to be mutated or lost before the predisposition is expressed. However, unlike other tumor suppressor genes, somatic mutations in these genes are uncommon in nonhereditary breast cancer. Furthermore, some lines of evidence suggest that there may be phenotypic consequences of haplo-insufficiency, which may be relevant to the process of carcinogenesis in these families. These observations, as well as the restricted tissue expression of the cancer predisposition, have not yet been clearly explained by a single model.


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