BRCA1: When DNA Fails

What Is BRCA1, and How Does It Function?

BRCA1 is a gene. Pathogenic variants in BRCA1 are associated with an increased risk of several cancers, including breast cancer. The BRCA1 gene codes for the breast cancer type 1 susceptibility protein, which is part of a group of proteins involved in repairing double-strand DNA breaks through a process called homologous recombination.

As cells continually grow and divide, they depend on accurate DNA repair to function properly. BRCA1 also contributes to cellular responses to DNA damage by helping regulate the cell cycle and, when damage cannot be adequately repaired, promoting apoptosis, or programmed cell death. In this way, BRCA1 helps prevent cells containing significant DNA damage from continuing to divide.

As a result, BRCA1 is known as a tumor suppressor gene. If this gene contains a pathogenic variant that disrupts its function, damaged DNA may not be repaired correctly. Over time, additional genetic changes can accumulate, increasing the risk of developing certain cancers, including breast cancer.

What Is a BRCA1 Gene Mutation, and How Does It Affect Breast Cancer Risk?

Everyone has two copies of the BRCA1 gene, one inherited from each parent. Changes in DNA, often called variants or mutations, can be passed on to both sons and daughters. When a variant is inherited, it is called a germline variant.

Not all BRCA1 variants have the same effect. Some are benign and have no known harmful effects, some are pathogenic and can increase cancer risk, and some are classified as variants of uncertain significance because there is not enough evidence to determine their effect. Pathogenic variants associated with inherited cancer risk typically occur in one copy of the gene.

BRCA1 and BRCA2 are among the genes most strongly associated with inherited breast cancer risk. Pathogenic variants can cause hereditary breast and ovarian cancer (HBOC) syndrome, increasing the risk of breast and ovarian cancers as well as certain other cancers, including prostate and pancreatic cancers. These variants can be inherited by people of any sex and can be passed through families.

How Does BRCA1-Associated Risk Vary Between Different Populations?

BRCA1-associated breast cancers are more likely to be diagnosed at younger ages and are more likely to be triple-negative breast cancer (TNBC), a subtype that can be more difficult to treat because it lacks three commonly targeted receptors: estrogen, progesterone, and HER2 receptors.

Black women are more likely than white women to develop breast cancer at a younger age and to be diagnosed with TNBC, despite similar rates of inherited pathogenic variants in BRCA1 and BRCA2.

Some pathogenic BRCA1 and BRCA2 variants originated in the ancestors of relatively isolated populations and were subsequently passed down through generations. These inherited variants are known as founder mutations. For example, approximately 2% of people with Ashkenazi Jewish ancestry carry one of three common BRCA1 founder mutations.

How Can BRCA1 Variants Be Identified, and What Are Some Preventive Measures?

Genetic testing for BRCA1 variants may be recommended based on a person's personal or family history of cancer, ancestry, or a known family mutation. Because inherited BRCA1 variants are present throughout the body, they can be detected using samples such as blood or saliva. Genetic counseling is recommended before testing to explain the potential benefits, limitations, and implications of genetic testing.

If a person has a pathogenic BRCA1 variant, each close relative may have a 50% chance of inheriting the same variant, depending on their relationship to the person who carries it. For people without cancer who carry a pathogenic BRCA1 variant, increased monitoring and preventive measures may be considered.

Some carriers choose risk-reducing surgery, such as bilateral risk-reducing mastectomy, which involves removing breast tissue, or risk-reducing salpingo-oophorectomy (RRSO), which involves removing the ovaries and fallopian tubes. Another option may be chemoprevention, which involves using medication to lower the risk of cancer in people who have not developed cancer.

The National Institute for Health and Care Excellence (NICE) recommends the use of medications such as tamoxifen and raloxifene in certain circumstances, depending on factors such as menopausal status and individual risk. Tamoxifen and raloxifene are known as selective estrogen receptor modulators (SERMs).

References

National Institute for Health and Care Excellence. Patient Decision Aid User Guide for Healthcare Professionals. NICE.

Breast Cancer Research Foundation. BRCA1.

Kim, et al. Annals of Laboratory Medicine, vol. 40, no. 2, 2020, p. 114. https://doi.org/10.3343/alm.2020.40.2.114.