Enhancing Breast and Ovarian Cancer Care: The Discovery of BRCA1 and BRCA2

Pathway to Discovery

Researchers long suspected that the risk of developing certain forms of cancer was inherited. Epidemiological evidence clearly showed that early-onset breast and ovarian cancers disproportionately affected women from certain families and populations, such as Ashkenazi Jews. This hinted at a hereditary cause for these types of cancer and suggested that a specific gene mutation could be the culprit.

BRCA gene mutations are inherited

Early genetic research by NCI-supported investigators Mary-Claire King, Ph.D., Mark Skolnick, Ph.D., and their colleagues associated a DNA region with hereditary breast cancer. Researchers then identified the BRCA1 gene within this region, which established a clear association between inheriting the mutant forms of the gene (known as germline mutations ) with increased cases of cancer. Later, germline mutations identified in another gene, BRCA2, were also associated with an increased risk of breast and ovarian cancers.

BRCA1 and BRCA2 mutations can lead to cancer

Both BRCA1 and BRCA2 belong to a class of genes known as tumor suppressor genes that function to prevent the growth of cancerous cells. Both play a role in cellular pathways that repair damaged DNA. Mutations in these pathways make cells more likely to accumulate DNA damage because they are less effective at repairing cells. This accumulated damage can lead to cancer.

Enhancing Cancer Care

Having a hereditary susceptibility does not mean that a person will develop a specific cancer, but the risk of developing that cancer may be higher for that person. Consequently, the identification of BRCA1 and BRCA2 mutations has provided some important changes in breast cancer screening and prevention. Now testing for these genes in affected families can help to inform decisions about preventive treatment.

Women with direct family members who have BRCA1 and BRCA2 mutations now have the option of being tested to find out if they are at increased risk for developing breast and ovarian cancers. But the decision to be screened for inherited gene mutations is not a simple one and dealing with the test results can be difficult.

Additionally, interpreting the results of genetic tests, including BRCA1 and BRCA2 mutations, is not always straightforward. Genetic counselors and other health care professionals can help by explaining complex test results to make them more meaningful to patients and their families.

Several studies have shown that BRCA1 and BRCA2 testing and risk assessment can be integrated into primary care. For instance, a screening approach followed by preventive interventions—such as risk-reducing surgery, when appropriate—may reduce the number of new cases of breast and/or ovarian cancers as well as the number of deaths from these cancers.

Turning Discovery into Health

Since the initial discovery that BRCA1 and BRCA2 gene mutations are linked to hereditary breast and ovarian cancers, genetic testing has been used to determine the potential or likelihood that family members are at increased risk of developing cancer. If cancer is present, it has also been used to determine whether the cancer was caused by a BRCA1 or BRCA2 mutation.

Research also has shown that BRCA1 and BRCA2 mutations may affect a tumor’s response to treatment. Current NCI-supported studies are examining whether rapid testing for BRCA1 and BRCA2 mutations along with diagnosis can inform treatment.

Preclinical studies and phase I and II clinical trials have shown that platinum chemotherapy, like cisplatin, and poly(ADP)-ribose inhibitors (PARP inhibitors), are effective at treating BRCA1 and BRCA2 breast cancers. The DNA damage caused by platinum chemotherapeutics cannot be properly repaired in cells with defective BRCA1 or BRCA2 genes, resulting in the death of those cells.

PARP inhibitors are part of a new generation of chemotherapy drugs that function by synthetic lethality. Alone, this drug does not cause cell death but it will do so in combination with another defect such as the BRCA mutation. The findings from trials testing PARP inhibitors—alone or in combination with platinum chemotherapy drugs—are promising.

Research to Practice: NCI's Role

• The identification of germline mutations in the BRCA1 gene as a hereditary predisposition to breast cancer by NCI-supported scientists was a landmark discovery.
• The finding that a small but significant number of cancers are caused by hereditary mutations was a critical development in determining the genetic underpinnings of many forms of cancer.
• Since the initial discovery, NCI continues to support a wide range of research into the function of the BRCA1 and BRCA2 genes.

Selected Resources

Clark CC, Weitzel JN, O’Connor TR. Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models.Mol Cancer Ther. 2012;11(9):1948-1958. [PUBMED Abstract]

Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990;250(4988):1684-1689. [PUBMED Abstract]

Nelson HD,Huffman LH, Fu R, Harris EL, Walker M, Bougatsos C. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. Evidence Syntheses, No. 37. Oregon Evidence-based Practice Center, Portland, OR. Rockville (MD): Agency for Healthcare Research and Quality. September 2005. [NCBI Bookshelf]

Pruthi S, Gostout BS, Lindor NM. Identification and management of women with BRCA mutations or hereditary predisposition for breast and ovarian cancer. Mayo Clin Proc. 2010;85(12):1111-1120. [PUBMED Abstract]

Petrucelli N, Daly MB, Feldman GL. BRCA1 and BRCA2 hereditary breast and ovarian cancer. GeneReviews™ [Internet]. Initial posting: September 4, 1998; Last update: September 26, 2013. [NCBI Bookshelf]

Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst. 2009; 101(2): 80-87. [PUBMED Central]

Sigal BM, Munoz DF, Kurian AW, Plevritis SK.A simulation model to predict the impact of prophylactic surgery and screening on the life expectancy of BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev. 2012;21(7):1066-1077. [PUBMED Abstract]

Wevers MR, Ausems MG, Verhoef S, et al. Behavioral and psychosocial effects of rapid genetic counseling and testing in newly diagnosed breast cancer patients: Design of a multicenter randomized clinical trial. BMC Cancer. 2011;11:6. [PUBMED Abstract]