by Alyson Warr

figures by Olivia Foster

One in eight women in the United States will develop breast cancer in her lifetime. This statistic makes breast cancer the leading cancer diagnosis for women in the US. With such staggering numbers, a focus on prevention is key: how can we stop breast cancer before it starts? One way is to develop fast and convenient methods of assessing breast cancer risk. If women could identify their individual risk, it could empower them to make choices about their own preventative care before a diagnosis, hopefully reducing the prevalence of the disease.

23andMe, the company known for its spit-and-mail ancestry test, is helping to make this goal a reality with their newly FDA-authorized direct-to-consumer genetic test for breast cancer risk. To complete the test, an individual must send a saliva sample to the company, from which DNA, the genetic material, is extracted. 23andMe then sequences, or reads, some of the molecules that make up the DNA. Specifically, the company is looking for changes, or mutations, in the DNA of two genes: BRCA1 and BRCA2.

Just five years ago, genetic testing for breast cancer cost thousands of dollars and could only be ordered by a healthcare provider. The test was so expensive partly because the company Myriad Genetics had a patent on the BRCA1 and BRCA2 genes, making them the only one that could provide this test. A monumental ruling by the Supreme Court in 2013 declared that genes are not patentable, which removed Myriad’s monopoly, and opened the door for other companies, like 23andMe, to produce genetic tests for BRCA mutations. Now, anyone can order a genetic test from 23andMe that provides some information on breast cancer risk for only $199. The company 23andMe is the first and currently only one to provide this service directly to the consumer without a physician order.

What are BRCA1 and BRCA2?

Mutations in BRCA1 and BRCA2, the BR east CA ncer genes, were discovered in the 1990s to be strongly associated with a high risk of breast cancer. These mutations are heritable, meaning they are passed from parent to child. The statistics are scary: about 70% of women with mutations in BRCA1 or BRCA2 will develop breast cancer before the age of 80.

Everyone has the BRCA genes, and normally they have a critical function inside our cells to keep us healthy: protecting our precious DNA, the blueprint for life. Our DNA can become damaged for a variety of reasons, including through random mistakes due to errors in our normal cell processes, or exposure to carcinogens like UV light or cigarette smoke. Damaged DNA can accumulate mutations, which can prevent our cells from functioning correctly. Mutations in DNA can be repaired by dedicated proteins, such as those encoded by the BRCA1 and BRCA2 genes (Figure 1).

If the BRCA1 or BRCA2 genes themselves are disrupted by mutations, though, our cells are not as effective at stopping random mutations from accumulating in the DNA over time. Most of these mutations will have no effect, but by chance, genes that are important for controlling cell growth could become mutated, disrupting the normal cellular rhythm of life and death. If enough of these consequential mutations accumulate, formerly healthy cells will start to grow uncontrollably. This unchecked growth can lead to the development of tumors (Figure 1). Even with early detection of tumors, it can be difficult to stop cancer once it has begun. That is where genetic testing comes in handy: it has the potential to identify those with high cancer risk before their cells mutate beyond recognition.

Figure 1: DNA damage in cancer DNA can be damaged by a variety of sources, including from carcinogens such as UV light or cigarette smoke. In a healthy cell, this damage is normally repaired by dedicated proteins, such as those encoded by the BRCA1 or BRCA2 gene. If the BRCA1 or BRCA2 gene itself is mutated, DNA is not repaired effectively when damaged. Over time, mutations can accumulate in the DNA, which can turn healthy cells cancerous.

Important limitations remain for breast cancer risk testing

While exciting and promising, the product developed by 23andMe, and breast cancer genetic testing as a whole, are still limited tools. They are not currently comprehensive enough to provide an accurate assessment of a person’s entire genetic risk for breast cancer.

23andMe’s test is limited in scope. It tests for just three mutations called single-nucleotide polymorphisms (SNPs): two in BRCA1 and one in BRCA2. These three SNPs are the most common mutations associated with an increased risk of breast cancer for individuals of Ashkenazi Jewish descent, where they occur in 1 in 40 individuals. These mutations are much less common for other ethnicities. There are nearly 200 more SNPs in tens of genes other than BRCA1 and BRCA2 that have been linked to altered breast cancer risk (Figure 2). 75 of these mutations were just linked to breast cancer risk in the past year. Additionally, there are numerous mutations in several genes for which scientists simply do not know the effect on breast cancer risk: these mutations are dubbed “variants of unknown significance (VUS)”. For example, there have been thousands of mutations identified in BRCA1 alone, and many are labeled as VUS. As such, it is possible for an individual who tests negative for the three SNPs chosen by 23andMe to have another mutation that increases breast cancer risk that was either not included in the test or is not yet well understood.

23andMe has also been criticized for providing data to consumers that may not be accurate. The company allows consumers to download additional data that are not verified, and consumers often use third-party websites to analyze these data to uncover more mutations. A recent study highlighted the abundance of false-positives in the extra data, meaning these data show the presence of mutations that do not actually exist in a person’s DNA. Confirming mutations with additional testing at the doctor’s office is critically important.

To fully understand the genetic causes of breast cancer, more research is necessary. So far, most of the studies that have researched breast cancer mutations have been performed in women of European ancestry, and the mutation-disease associations in that racial background may not hold true for other women. If scientists want to generate the most accurate information and ensure genomic medicine can serve all populations, future studies need to emphasize inclusivity across racial and ethnic backgrounds.

It is also important to keep in mind that only about 5-10% of breast cancer is considered to be genetically heritable, meaning 90-95% of women who develop breast cancer do not have an inherited mutation. These women develop cancer for other reasons: environmental toxin exposure, lifestyle choices, other disease risks, and so on. The main driver of breast cancer in women, then, is not mutations in BRCA1, BRCA2, or any other genes, but rather non-heritable factors (Figure 2). This means that despite genetic test results, women should continue to consult with their physician over their life to monitor their breasts with mammograms.

Figure 2: Breast cancer heritability Most (90-95%) of breast cancer cases are not caused by heritable mutations. For the 5-10% of breast cancer cases that are genetically inherited, there have been 200 mutations called single-nucleotide polymorphisms (SNPs) linked to altered breast cancer risk. The new genetic test for breast cancer risk offered by 23andMe tests for just 3 of these SNPs.

The future of genetic testing: Precision prevention

In the near future, it is likely that 23andMe and other companies will expand their testing portfolio to include sequencing a larger number of SNPs, other types of mutations, or even the entirety of an individual’s DNA, where every mutation in every gene can be assessed at once. Modern DNA sequencing technology will make this possible: it took an international team of scientists 13 years and $3 billion to sequence the first human genome. Now, it can be done for as little as $100 by one scientist. Genetic tests, powered by sequencing technology, will become a useful tool for physicians working towards the goal of precision prevention, where patients can understand their unique risk of disease and take personalized preventative measures accordingly.

Alyson Warr is a PhD candidate in the Biological and Biomedical Sciences Program at Harvard Medical School and the co-director of Science in the News.

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This article is part of the 2018 Special Edition — Tomorrow’s Technology: Silicon Valley and Beyond