BRCA 1 and 2--A Genetic Link to Familial Breast and Ovarian Cancer

, , , Duke University Medical Center

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Cancer Genetics Overview

Uncontrolled cellular proliferation can result when defects occur in genes that are critical to normal growth control. Two principal classes of these regulatory genes have been implicated in neoplastic development: proto-oncogenes and tumor suppressor genes. Proto-oncogenes encode proteins that stimulate DNA synthesis and cell division. These proteins include peptide growth factors and their cellular membrane receptors; second-messenger cascade proteins, which transmit information from the cell membrane to the nucleus; and nuclear transcription factors, which control gene expression by binding to DNA. Activation of proto-oncogenes to oncogenes--by amplification, translocation, or point mutation--can result in unrestrained cellular proliferation and tumorigenesis. Because only 1 copy of a proto-oncogene needs to be activated to promote tumor growth, proto-oncogenes are said to act dominantly at a cellular level. Proto-oncogenes are thought to play little role in inherited cancer syndromes, with the exception of the RET proto-oncogene in multiple endocrine neoplasia (MEN-II).[10]

Tumor suppressor genes are the second class of genes integral to normal growth control. They encode proteins that function to restrain proliferation. Tumor suppressor genes can be inactivated by point mutation, deletion, or loss of expression. Since both copies of the gene need to be inactivated to result in tumorigenesis, the family of tumor suppressor genes is said to act recessively at a cellular level. Thus, mutations in tumor suppressor genes can be inherited in the germline of an individual, producing a familial cancer predisposition. Unrestrained cellular proliferation does not occur until the remaining functional copy of the gene is inactivated--often by deletion of all or part of its chromosome.[11] Alternatively, somatic mutational inactivation of both copies of a tumor suppressor gene can result in the development of cancer in an individual born with 2 wild-type, or normal, copies of the gene. BRCA1 and BRCA2 are thought to act as tumor suppressor genes.


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