BRCA1 and BRCA2 genes and cancer

• ALSO KNOWN AS: Breast cancer susceptibility genes; breast cancer 1, early onset; breast cancer 2, early onset

DEFINITION: BRCA stands for breast cancer susceptibility. BRCA1, the first breast cancer susceptibility gene, was identified and cloned in 1994. A second breast cancer susceptibility gene, BRCA2, was discovered soon after. Identification of BRCA1 and BRCA2 as breast cancer susceptibility genes has had a profound impact on understanding the disease. The immediate clinical use of their discovery for both diagnosis and accurate assessment of increased risk through screening has been one of the foremost success stories in the fight against cancer.

Familial disease: The American Cancer Society reported in 2021 that between 5 and 10 percent of breast cancers are hereditary. The BRCA mutations can be inherited from either the maternal or the paternal side of the family. The National Breast Cancer Foundation estimated that 316,950 women and 2,800 men in the United States would be diagnosed with invasive breast cancer in 2025.

Mutations in BRCA1 and BRCA2 increase a woman’s lifetime risk of not only breast cancer but also ovarian, colon, uterine, and fallopian tube cancers. Women with an inherited alteration in one of these genes have an increased risk of developing these cancers before menopause. Altered BRCA2 poses a greater risk in men than altered BRCA1. Men with altered BRCA2 are at a higher risk of breast cancer and prostate cancer. Alterations in the BRCA2 gene have also been associated with increased risks of lymphoma, melanoma, and cancers of the pancreas, gallbladder, bile duct, and stomach in both men and women.

Risks and incidence: The National Breast Cancer Foundation estimates that one of every eight women will be diagnosed with breast cancer in their lifetime, and they estimate that one in every four hundred women has an altered BRCA1 or BRCA2 gene. Women with the mutated gene have a 45 to 85 percent chance of developing breast cancer. The ovarian cancer risk by age seventy is 39 percent in BRCA1 carriers and 11 to 17 percent in BRCA2 carriers, compared with 2 percent in the general population. Among men, the breast cancer risk is 5 to 6 percent for carriers, one hundred times that of the general male population, as reported by the US Food and Drug Administration. In carriers, risks for colon, pancreatic, prostate, and stomach cancers are also elevated.

The likelihood that breast or ovarian cancer is linked with BRCA1 or BRCA2 mutations is highest in families with a history of multiple cases of breast and ovarian cancer, particularly involving a mother, sister, or daughter; diagnosis of breast cancer before the age of fifty; presence of male breast cancer in the family; two or more primary cancers, such as breast and ovarian cancers, or bilateral breast cancer (separate cancers in each breast) in an individual; other multiple cancers in the family, especially prostate cancer; and an Ashkenazi (central and eastern European Jewish) background. It is important to note that not every woman with this sort of background will carry a defective BRCA1 or BRCA2, and not every cancer that occurs in such families will be due to a BRCA1 or BRCA2 defect. Additionally, not all women who carry a BRCA1 or BRCA2 mutation will develop breast or ovarian cancer.

Furthermore, the National Cancer Institute (NCI) states that mutations in BRCA genes account for breast or ovarian cancers in 45 percent of families with a history of breast cancer and up to 90 percent in families with a history of both breast and ovarian cancers. BRCA2 mutations account for breast cancer in about 35 percent of families with a history of breast cancer. Studies suggest that women who develop breast cancer before the age of fifty have a one in four chance of carrying a BRCA1 or BRCA2 mutation if they have any relative who also develops the disease before the age of fifty. There is a 50 percent chance that mutant carriers will transmit the mutated gene to their offspring.

BRCA1-related breast cancer appears to be more aggressive than other types of breast cancer and has a poorer prognosis, and most BRCA1-related ovarian cancers are invasive. Some characteristics of hereditary breast cancer, such as how it occurs at an earlier age, more often affects both breasts, and is associated with other cancers, make it clinically distinct from sporadic cancer.

History: BRCA1 and BRCA2 were identified by linkage analysis of families with multiple cases of early-onset breast and ovarian cancer. BRCA1 is 5,592 kilobases long with 24 exons, and BRCA2 is twice as long with 10,254 kilobases and 27 exons. More than twenty thousand different variants scattered throughout BRCA1 and BRCA2 had been identified by 2019, as reported by The BRCA Exchange. These alterations tend to be distinct, and in general, most families have a unique alteration. Mutations anywhere along either gene are associated with an increased risk of breast cancer. Some evidence suggests that mutations in the 5′ end of BRCA1 and mutations in exon 11 of BRCA2 might be associated with ovarian cancer. Alterations in certain regions of the BRCA2 gene are known to predispose individuals to a greater risk of ovarian cancer in women and prostate cancer in men, as compared with alterations in other parts of the gene. This suggests differences in patterns of cancer between individuals with a BRCA1 mutation versus a BRCA2 mutation.

Of the thousands of alterations identified in each gene (BRCA1 and BRCA2), three "founder mutations" have been identified in Ashkenazi Jewish families with a history of breast cancer. These alterations are 185delAG and 5382insC (BRCA1) and 6174delT (BRCA2). N. Petrucelli, M. B. Daly, and G. L. Feldman reported in Gene Reviews (2013) that the estimated frequencies of the three alterations in the general Ashkenazi population are 1.1 percent, 0.1 to 0.15 percent, and 1.5 percent, respectively.

Cellular function: BRCA1 and BRCA2 are tumor-suppressor genes, and the BRCA proteins are involved in a multitude of key cellular processes. Research has demonstrated the involvement of BRCA1 and BRCA2 proteins in complexes that activate repair of double-strand breaks and initiate homologous recombination, suggesting a key role of BRCA proteins in maintaining genome stability and integrity. In response to deoxyribonucleic acid (DNA) damage, BRCA1 is engaged in the transcriptional regulation of several genes, such as P21 (CDKN1A) and GADD45, which activate cell-cycle checkpoint-induced replication arrest to allow for repair. It is unclear why a defect in BRCA predisposes predominantly to cancer of the breast and ovary, even though the known functions of BRCA proteins are essential to all cell types.

Whether estrogen, a known promoter of sporadic breast cancer, affects the risk of BRCA1- and BRCA2-related breast cancers is not clear. Given that factors that contribute to enhanced exposure to estrogen, such as early onset of menarche and late menopause, correlate with a higher incidence of breast cancer and that premenopausal oophorectomy (the surgical removal of the ovaries) exerts a preventive effect, an association is suggested between BRCA1 and BRCA2 and estrogen receptor alpha (ERα).

Prevention: The best opportunity to reduce mortality is through early detection. Early screening for breast cancer, beginning at age twenty-five to thirty-five, is recommended for women who have BRCA mutations. Clinical examinations, mammograms, or magnetic resonance imaging (MRI) may be used to detect breast changes.

Preventive mastectomy and preventive oophorectomy to reduce the risk of breast cancer and ovarian cancer, respectively, are possible options. Although oophorectomies are usually performed to reduce ovarian cancer risk, having an oophorectomy before menopause also reduces the risk of breast cancer. Removal of ovaries is associated with a decrease in the production of the hormones estrogen and progesterone, which play a major role in breast cancer progression.

For a premenopausal woman with a BRCA mutation, oophorectomy may reduce the risk of breast cancer mortality by as much as 50 percent and may reduce the risk of ovarian cancer mortality by as much as 80 percent, according to the JNCI Cancer Spectrum study published in 2019. However, it is important to note that prophylactic surgery reduces but does not eliminate the risk of cancer and carries additional risks related to surgery. Behaviors that can reduce breast cancer risk in general include regular, vigorous exercise, decreased alcohol consumption, early childbirth, and breastfeeding for more than twelve months, although the effects of these on BRCA mutation carriers are unknown.

Even though tamoxifen is known to reduce the risk of invasive breast cancer by 50 percent in patients with an increased risk of developing the disease, limited data are available regarding the use of tamoxifen for chemoprevention in women with BRCA1 and BRCA2 alterations. One study found that tamoxifen reduced breast cancer incidence among healthy BRCA2 carriers. However, another study found that tamoxifen use beginning at thirty-five years or older did not reduce breast cancer incidence among healthy women with inherited BRCA1 mutations. Therefore, further studies are necessary.

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