The New BRCA1/2 Landscape

Jane de Lartigue, PhD | December 13, 2014
DNA strandAs one of the most significant predictors of hereditary breast and ovarian cancer, the BRCA1/2 genes have become the poster child for genetic testing, thrust into the limelight by a high-profile court battle and a celebrity’s disclosure.

In the past 18 months, the floodgates for testing options have opened, as companies seek to enter the diagnostic market in the wake of the US Supreme Court’s June 2013 ruling that “naturally occurring” human genes are a “product of nature” and cannot be patented, breaking Myriad Genetics’ monopoly on BRCA1/2 gene testing.

And, demand for the testing also has risen as a result of actress Angelina Jolie’s disclosure that she opted to undergo a double mastectomy after BRCA1/2 testing revealed the presence of a mutation that significantly increased her risk of breast cancer.

Yet even as BRCA1/2 testing becomes more widely available in oncology practice, fresh questions about interpreting the results of these assays and a debate about which individuals should be screened for mutations have arisen.

BRCA’s Many Functions

Genetic alterations are central to the development of cancer and, though most are acquired over a person’s lifetime, between 5% and 10% are inherited germline mutations that can increase the lifetime risk of particular cancer types. Mutations associated with more than 50 hereditary cancer syndromes have been identified to date and testing for such mutations can help to assess an individual’s cancer risk.

BRCA1/2 genes are tumor suppressor genes that orchestrate a variety of cellular processes to protect the genome from accumulating damage that is a hallmark of malignant transformation. The best-understood role of the BRCA1/2 genes is in the repair of double-strand breaks (DSBs) in DNA.

When mutations occur in these genes that impact protein function, they are unable to repair damaged DNA, rendering the cell susceptible to further genetic alterations, and ultimately leading to genomic instability and the formation of cancerous cells.

Thousands of BRCA1/2 mutations have been identified to date throughout the coding regions of these genes. Most of the mutations that have been implicated in the development of cancer are frameshift mutations involving the insertion or deletion of a single base or a small number of bases that alter the way the DNA is read by the cell and result in the truncation of the protein, ultimately compromising its function. There are a number of other less common mutation types that occur, however, including large rearrangements, which primarily consist of the deletion or duplication of segments of DNA.

Defining Pathogenic Mutations

BRCA1/2 alterations are generally classed as pathogenic on the basis of observed frequencies in cases of cancer compared with healthy controls. Though sporadic BRCA1/2 mutations are thought to be relatively rare, inherited germline mutations are more common.

Overall, the prevalence of pathogenic BRCA1/2 mutation carriers in the general population is estimated to be between 1 out of every 400 persons and 1 out of 800 persons. There are a number of founder mutations, which are high-frequency mutations that are particular to a specific population such as the 185delAG, 5382insC, and 6174T mutations, that are found at a frequency of 1 out of 40 persons in the Ashkenazi Jewish population.

Complexities of BRCA1/2 Testing

Complexities of BRCA1/2 Testing

The detection of variants of unknown significance (VUS) clouds interpretation of BRCA1/2 testing results, prompting some researchers to propose an integrated model for analyzing VUS (above).
ER indicates estrogen receptor; HER2, human epidermal growth factor 2; PR, progesterone receptor; VUS, variant of unknown significance.

Source: Calò V et al. Cancers (Basel). 2010;2(3):1644-1660.



BRCA1/2 mutations are autosomal dominant, meaning an individual only needs to inherit a single defective copy of the gene from a parent to have an increased cancer risk.

BRCA1/2 mutations are particularly significantly associated with increased risk of breast and ovarian cancer. A genetic link between chromosome 17 (where BRCA1 resides) and breast cancer risk was first uncovered in the 1990s and no predictor of risk of developing these cancer types has proved to be as powerful.

Compared with the general population, in whom the currently estimated lifetime risk of breast and ovarian cancer are 12% and 1.4%, respectively, individuals with inherited BRCA1/2 mutations have a substantially increased risk; by age 70, the risk of breast cancer is estimated to be 55% to 65% for BRCA1 carriers and 45% for BRCA2 carriers, while the risk of ovarian cancer is 39% for BRCA1 carriers and 11% to 17% for BRCA2 carriers.


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