After the Test

Angelina Jolie writes in an op-ed about her decision to undergo preventive double mastectomy following genetic testing for breast cancer.

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Angelina Jolie's highly

Angelina Jolie's highly publicized decision to have radical surgery based on the presence of a mutation in her BRCA1 gene is a preview of what is likely to become more common place in the future with companies that are pushing genetic testing. In general, woman have about a 1 in 9 chance of developing breast cancer in their life-time, and roughly 2.2% of breast tumours have a point mutation, deletion or insertion in their BRCA1 gene. Running the numbers, this indicates that in the general female population in the United States alone, over a third of a million women (156 million / 9 x 0.022= 382,333) would undergo similar surgery if they followed the advice of Ms. Jolie and her doctors.

Full blown cancer arises from multiple mutations that coincide within exactly the same genome on different genes that can complement each other to promote the disease. The BRCA1 gene encodes a tumour suppressor protein (TSP), which can loose its functionality when it is mutated. TSP's commonly act to block cell growth and division, essentially acting as brakes on cancer. Much of the human population is likely born with compromising mutations in one or more of probably more than a hundred different TSP genes that we know of today. The real problem arises when additional mutations accumulate during a person's lifetime with exposure to chemical carcinogens and radiation. In particular, driver mutations in oncogenes can lead to a gain of function in the proteins that they encode, which can facilitate the growth and spreading of tumours. Our knowledge of the number of tumour suppressor genes and oncogenes is slowing improving with current cancer research and we are starting to identify the specific mutations that are the most problematic. However, this knowledge is still pretty rudimentary. Consequently, it is really hard to assign specific probabilities for the development of cancer based on the analysis of just a couple of genes for the whole population, never mind for a single individual.

Other tumour suppressor genes are actually much more commonly mutated in human cancers than BRCA1 or BRCA2. For example, the p53 and RB1 genes are mutated in about 29.8% and 4.7%, respectively, in all human tumours. In breast cancer specifically, p53 and RB1, respectively, are mutated 23% and 3.9% of the time. By contrast, BRCA1 and BRCA2 mutations show up in only 2.2% and 1.3% of human breast tumours. Testing for especially common or highly risky cancer-driver mutations can certainly alert individuals that are at higher risk to have more frequent check ups and actually test for the presence of cancer, and the prognosis is much better with earlier diagnosis. Moreover, adopting a healthier life-style can cut the risk of cancer by approximately half.

The decision to have a preventive double mastectomy without evidence of actual breast cancer is obviously a personal choice with benefits and consequences. Epidemiology studies have indicated that breast cancer survival rates from lumpectomies are as high as full mastectomies. Careful monitoring for breast cancer, for example, with highly sensitive proteomics-based tests and imaging can provide very early diagnosis with better patient outcomes. In view of how common many disease-related mutations may actually be within our population, it is critical that tests for these mutations put the risks into perspective and radical solutions are not taken unnecessarily. With the remarkable advancements in modern medicine, it is worth considering that deadly diseases today, could become relatively minor or at least manageable problems in the near future.

It is very regrettable that,

It is very regrettable that, in our post-genomics world, the only option available was double radical mastectomy. One priority should be enhanced federal research funding for studying the causes of, and developing new treatments for, cancers of all sorts. This will be difficult in an era of sequestration cuts.

Another priority (touched on by Ms. Jolie but not explained) was that the reason for the extremely high price of genetic testing for BRCA-1 and -2 testing is that Myriad Genetics holds patents on BRCA-1 and BRCA-2 genes. These patents give Myriad exclusive rights for genetic testing of these genes. Consequently, no other companies are allowed to develop or offer better or cheaper genetic testing for these genetic risk factors.

The Supreme Court recently revisited the whole notion of patents for human genes. In my view, there is a powerful need to eliminate or redefine the legal right of for-profit companies to patent human genes. NO person, whether an individual or a corporate entity, has even invented a human gene. Human genes exist in Nature without any help from any biotech company. Were gene patenting restricted or removed, other commercial players could enter the BRCA genetic testing market and reduce the price of genetic testing for all women at risk. Once the dubious privileges granted to corporations by the legal right to patent human genes are more widely & critically understood, things will surely change for the better for women worldwide who are at-risk for breast cancer.

For more information, see:
Rosenfeld and Mason (2013). "Pervasive human patents cover the entire human genome." Genome Medicine, 5:27.
Skloot R (2010). The Immortal Life of Henrietta Lacks. NY: Random House.

I agree that BRCA1/2 genetic

I agree that BRCA1/2 genetic testing can reduce the risk of breast and ovarian cancer significantly in affected families. It is very important that someone in the family who already have breast cancer must first be tested to identify the family-specific mutation, which can then be screened for in unaffected family members to identify or exclude the familial risk. In some populations a small number of BRCA mutations are responsible for breast cancer in the majority of affected individuals, which means that the test is much cheaper. We developed a online service accessible at www.gknowmix.com to address all these aspects to ensure that the appropriate test is done after genetic counselling that is preferably done in person or alternatively by phone or Skype. It is unfortunately that the price of the test is so high in the USA, fortunately this is not the case in South Africa as the genes have not been patented here.

Given significant family

Given significant family history supporting pathogenicity of a variant found in one of the BRCA genes, I guess extensive surgery is perhaps the most successful (despite being highly invasive) option. Most of what one respondent said about cancer, breast cancer, other tumor genes, etc is not directly relevant in this situation, where the documented family history plus genetics are presumably paramount. Disclosure: former employee of Myriad (in research though, not clinical diagnostics).

Without specific information

Without specific information about Angelina Jolie's genome and life style, it is really difficult to comment on her specific case. The fact is that most people today have parents, grandparents or at least relatives that have been afflicted with cancer. My major point is that there are many other tumour suppressor genes that have higher rates of association with breast cancer than BRCA1 and BRCA2. As more genomic information with genetic testing becomes available, I fear that a significant portion of the population will resort to measures that are expensive, unnecessary and not really in their the best interests.