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See also: BRCA1 gene, carcinoma of the breast.
Familial clustering of breast cancer has long been recognized. Familial breast cancers are characterized by onset before age 45 and by occurrence in three or more close relatives and in members of more than one generation. About 5% of all breast cancers are due to the inheritance of dominant susceptibility genes, particularly BRCA1 and BRCA2. Whereas spontaneous mutations of the BRCA genes are uncommon, hundreds of inherited mutations have been discovered on each gene. The clinical significance of many of them is unknown. Because these are autosomal chromosomes, men as well as women can inherit and pass on the BRCA mutations. The histology of breast cancer in women with BRCA1 and BRCA2 mutations differs from that of sporadic cases. The proportion of medullary carcinomas is higher among BRCA1-associated breast cancers than among all breast cancers. BRCA1 and BRCA2 are tumor suppressor genes, inhibiting tumor development when functioning normally. Both are large genes, with a prodominance of two distinct mutations for BRCA1 and one for BRCA2. Despite the high penetrance of the mutant gene, not all carriers develop cancer. Hormonal, environmental, reproductive, and other genetic factors may influence penetrance. Estradiol increases cell proliferation and production of the BRCA1 gene expression. Observed mutations are distributed throughout the gene; the majority are insertions, deletions, or nonsense mutations. Two common changes (185delAG and 5382insC, in exons 2 and 20, respectively) account for approximatesly 19% of BRCA1 mutations. The former of these is present in about 1% of Ashkenazic Jews and is responsible for about 32% of familial breast cancer in Jews. It is also found in 13% of ovarian cancer patients with no family history of breast or ovarian cancer, and in 30% of those with family histories suggesting inherited disease. BRCA1 mutations cause a threefold increase in the risk of prostate cancer and, in people of both sexes, a fourfold increase in the risk of colon cancer. The BRCA2 6174delT mutation is estimated to be present in 1.3% of Ashkenazic Jews. The risk that a woman with a BRCA1 or BRCA2 gene mutation will develop breast cancer at some time in her life is believed to be 10-30%. In addition, 15-20% of women with the BRCA1 mutations will develop ovarian cancer. Although testing for BRCA genetic mutations is available, most authorities do not recommend routine screening except in women with a strong family history of cancer. Women found to have BRCA genetic mutations have been advised to begin breast self-examination at age 18 and regular annual physician examinations and mammograms at age 25. The benefit of radiologic screening must be weighed against the possible effect of radiation on the BRCA1 or BRCA2 allele. MRI has been recommended by some authorities for annual surveillance of women at high risk. There is insufficient evidence to support the belief that periodic screening of women at high risk of ovarian cancer with serum markers, transvaginal ultrasound, or pelvic examinations can reduce mortality from ovarian cancer. Tamoxifen has been shown to reduce the risk of breast cancer in genetically predisposed women by as much as 50%.
See also: BRCA1 gene, carcinoma of the breast