HOW DO THE BRCA1 AND BRCA2 GENES CAUSE CANCER?
BRCA1 and BRCA2 have received a lot of attention because of the link between harmful mutations in these genes and breast and ovarian cancer. BRCA1 and BRCA2 encode tumor suppressor proteins. One of the functions of these proteins is to help repair damaged DNA and maintain genomic stability. Women who are born with one defective copy will often lose the function of the remaining copy at some point in time, and this then leads to chromosomal changes and cancer at a very high incidence. The frequency of women with single BRCA1 and BRCA2 germline mutations developing breast or ovarian cancer before age 70 is over 80%.
Some women who inherit harmful mutations in BRCA1 or BRCA2 opt for surgical removal of their breasts and/or ovaries to reduce their risk of developing cancer. The possible presence of germline BRCA1 or BRCA2 mutations may be suspected in individuals with close family members that developed breast and/or ovarian cancer at an early age. Such individuals can get tested to see if they carry a harmful BRCA1 or BRCA2 mutation. Genetic testing is helpful but not always conclusive. Sequencing may reveal a mutation in BRCA1 or BRCA2, but it may not be possible to determine whether the mutation is harmful. Furthermore, BRCA1 and BRCA2 mutations are not always inherited; sometimes they occur spontaneously, that is, as somatic mutations, and, therefore, may not be detected in the blood or saliva sample used for genetic testing because they are not present in every cell of the body.
Although mutations in BRCA1 and BRCA2 are established causes of familial breast cancer, they still only account for 15%–20% of such cases (Figure 1). Mutations in other genes also can be responsible for familial cancer but are present at lower frequency. It is also possible that undiscovered mutations in the regulatory regions of BRCA1 and BRCA2 account for additional cases of familial cancer. A recent study of women with a family history of breast cancer, who had normal BRCA1 and BRCA2 revealed that 10% had mutations in an additional 42 genes. Thus, gene panels that go beyond BRCA1 and BRCA2 are likely to be useful in determining an individual’s genetic predisposition for breast cancer. Much more work needs to be done, however, to elucidate the genetic basis of breast cancer, particularly for the 70% of familial breast cancer cases for which no candidate genes have been identified.
Figure 1. Mutations in BRCA1 and BRCA2 each account for approximately 10% of familial breast cancer. Mutations in another 42 genes account for another 10%; the cause of the remaining 70% is not known.