BRCA

20 Years After BRCA: What We’ve Learned About Genetics and Breast Cancer .

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Twenty years ago, scientists announced the discovery of BRCA1, which arguably has become the best-known cancer susceptibility gene in the world. When inherited in a mutated form, the gene sharply increases a woman’s chances of developing breast orovarian cancer, often at an early age. The discovery has changed the way women with a family history of breast and ovarian cancer approach these diseases, helping them better understand their risk and the options for reducing it. It also presents them with complex choices about sharing genetic test results with family members who may also carry the mutated gene.

The hunt for BRCA1 began in earnest in 1990, after Mary-Claire King of the University of California at Berkeley discovered a genetic link to breast and ovarian cancer on chromosome 17. That set in motion a worldwide competition to scour chromosome 17 for the actual gene – dubbed BRCA1 for BReast CAncer 1. In August 1994, Mark Skolnick, PhD, of Myriad Genetics in Salt Lake City, announced his group had found BRCA1 and mapped its DNA sequence.

Huma Q. Rana, MD, medical director for Dana-Farber's Center for Cancer Genetics and Prevention.

While these discoveries led to the identification of BRCA1 – and, a year later, to a secondbreast cancer susceptibility gene, BRCA2 – their roots lay in research begun decades earlier by Dana-Farber’s Frederick P. Li, MD. With his colleague Joseph Fraumeni, MD, Li found that abnormalities in certain inherited genes explained why some families have a pattern of cancer across the generations.

Although only about 5-10 percent of women with breast cancer carry inherited mutations in BRCA1 or 2, those whodo have these harmful mutations face a substantially elevated chance of developing a second breast cancer or ovarian cancer. About 12 percent of women in the general population will develop breast cancer at some point during their lives, research shows. By contrast, 55-65 percent of women who inherit a harmful BRCA1 mutation and about 45 percent who inherit a harmful BRCA2 mutation will develop breast cancer by age 70.

The picture is similar for ovarian cancer. About 1-2 percent of women in the general population develop ovarian cancer. Compatively, 39 percent of women who inherit a BRCA1 mutation and 10-20 percent who inherit a BRCA2 mutation will develop ovarian cancer by age 70.

The discovery of BRCA1 and BRCA2 has removed some of the unknowns about breast and ovarian cancer risk and clarified the choices available to women and men who test positive for harmful mutations in these genes. Those choices include more frequent breast exams; enhanced and early breast imaging/screening; surgery to remove the breasts as well as the ovaries; and medications such as tamoxifen, which, according to several studies, can lower the risk of breast cancer in BRCA1 and 2 mutation carriers.

In the years since the discovery of BRCA1 and 2, research has identified the role these genes normally play in cells, and how mutations disrupt that role, potentially leading to cancer. Researchers led by Dana-Farber’s David Livingston, MD, for example, have shown BRCA1 and 2 to be “tumor-suppressor” genes that help repair damaged DNA within cells. When a mutation interferes with such repairs, the accumulation of DNA damage can send cells on a course to cancer.

Research into the basic workings of BRCA1 and 2 has led to some promising approaches to treating breast and ovarian cancers. Recent studies by investigators at the Susan F. Smith Center for Women’s Cancers at Dana-Farber have shown that chemotherapy agents with platinum, combined with drugs known as PARP inhibitors, are effective at treating BRCA1 and 2-related breast cancer.

Testing positive for BRCA1 or 2 mutations can raise concerns not only about one’s own health but also that of relatives who may also have inherited the mutations. Many cancer centers provide genetic counseling services to help people work through questions about how – or whether – to talk with loved ones about testing.

Who Owns Human Genes?

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Angelina Jolie’s recent disclosure that she had undergone a prophylactic double mastectomy following a positive test for a BRCA1 mutation (which increases lifetime breast cancer risk by 60%-87%) prompted a national conversation about genetic testing and preventive surgery.1 Tests for BRCA1 and BRCA2 cost more than $3000, placing them beyond the reach of many women. The high cost is partly a consequence of intellectual property protection afforded to Myriad Genetics Inc, which sequenced the genes and developed the testing capability.

The Patent Act permits exclusive control for a limited time (currently 20 years) of any “process, machine, manufacture, or composition of matter.” Following a US Supreme Court ruling upholding the patentability of a microbe that dissolves oil,2 the US Patent and Trademark Office (USPTO) began routinely granting gene patents. On June 13, 2013, the US Supreme Court unanimously held that extracted and isolated DNA is a product of nature and not eligible for patent, but that complementary DNA (cDNA), which is synthetic DNA created in the laboratory, is patentable because it is not naturally occurring.3

The compromise ruling acknowledged difficult issues in a simmering controversy. Granting commercial rights over naturally occurring biological products seemed unethical because industry should not be able to control access to unaltered materials found in nature. However, failure to afford intellectual property protection could stifle innovation, robbing entrepreneurs of financial incentives for discovery. Myriad lost the exclusive right to isolate the BRCA1 and BRCA2 genes of individuals, but maintained the right to its unique method of synthetically creating BRCA cDNA to produce and market its tests.

SHAPING THE COURSE OF RESEARCH

The Court’s decision will influence the future of human genome research. The rapidly evolving capacity to sequence the genome will usher in an era of relatively inexpensive screening for multiple risks. Myriad plans to phase out BRCA gene tests by mid-2015, marketing instead a more comprehensive test panel for 25 genes. Competitor laboratories will also introduce panels, ultimately enabling detection of hundreds of genes.5

Research will be affected beyond human genetics; for example, researchers will likely challenge existing patents on bacterial genes. The Court’s decision may also affect intellectual property protection afforded to a wide variety of naturally occurring substances, such as innovations derived from microorganisms or plants.

Ideally, the law ought to facilitate science as well as make lifesaving technologies more affordable and accessible. The future should be filled with excitement as scientists and innovator companies expand the horizon of medical technologies to prevent, detect, and treat human diseases. Achieving this vision will require massive public investment, private innovation, and the useful application of new diagnostics and pharmaceuticals through the health care system.

REFERENCES

1

Jolie A. My medical choice. New York Times. May 14, 2013; A25.

2

Diamond v Chakrabarty, 447 US 303 (1980).

3

Association for Molecular Pathology v Myriad Genetics, 569 US ___ (2013).

4

Mayo Collaborative Services v Prometheus Laboratories, Inc, 132 S Ct 1289 (2012).

5

Pollack A. After DNA patent ruling, availability of genetic tests could broaden. New York Times. June 14, 2013; A16.

Source: JAMA

 

 

Does Diagnostic Radiation Increase Breast Cancer Risk in Women with BRCA Mutations?

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European questionnaire-based study leaves the question unanswered.

Because ionizing radiation can damage DNA, diagnostic x-ray exposure in individuals with defects in DNA repair mechanisms (such as those associated with BRCA1 and BRCA2 mutations) could lead to excess risk for cancer. Investigators surveyed women with documented BRCA1/2 mutations in the Netherlands, France, and the U.K. to evaluate any association between radiation exposure and later development of breast cancer. Questionnaires were administered to BRCA1/2 carriers from 2006 to 2009 to elicit their recollections of the type and number of diagnostic procedures they had received in their lifetimes. Estimates of radiation doses to the breast during each type of diagnostic procedure (mammography, fluoroscopy, and computed tomography and conventional radiography of the chest or shoulder) were used to determine total cumulative dose. Cases that were diagnosed >5 years before completion of the study questionnaire were excluded to prevent survival bias.

Of the 1993 participants, 43% (mean age, 49.7) had received diagnoses of breast cancer. Self-reported exposure to any form of diagnostic radiation before age 30 was associated with significantly higher risk for breast cancer (hazard ratio, 1.90; 95% confidence interval, 1.20–3.00), and risk rose with increasing cumulative dose. A history of mammography before age 30 was associated with nonsignificantly increased risk for breast cancer (HR, 1.43; 95% CI, 0.85–2.40). No evidence of excess risk was found for diagnostic radiation exposure between ages 30 and 39.

Comment: As with other epidemiologic studies of diagnostic radiation and risk for breast cancer in BRCA1/2 mutation carriers, the results of this study are inconclusive. The retrospective questionnaire design is subject to recall bias, especially given that women were asked to recollect events occurring up to 30 years earlier. Moreover, no attempt was made to document the date and type of radiologic tests that were reported. Furthermore, estimates of cumulative radiation dose were hypothetical and subject to wide variation based on factors in individuals as well as facilities. Until further data are obtained, the National Comprehensive Cancer Network recommendation of screening with magnetic resonance imaging and mammography in BRCA mutation carriers beginning at age 25 should be followed.

Source: Journal Watch Oncology and Hematology