The last few weeks, I’ve discussed how the efforts of the human genome project and next-generation sequencing have contributed to significant progress in the field of personalized medicine. Identifying the precise genetic basis of a disease can help scientists understand how the disease manifests, can help doctors diagnose and treat patients earlier, and could potentially unlock the ability to remove the disease through genetic editing. Many diseases have a genetic basis and not all of them are fully understood. Within this series, I will endeavor to uncover some of what scientists have learned about genetic diseases, disorders, and risk factors. I won’t be able to cover everything, as there are over 6,000 genetic diseases (not even including heritable risk factors that contribute to disease), but I will try to hit the highlights. This week, I want to talk about the genetic element of breast cancer risk. We tend to think of cancers as mainly environmental or random, but many cancers have genetic risk factors that can run in families. There are also genetic elements that can affect how aggressive a cancer may be or how it can be effectively treated. Research on these genetic factors began long before the human genome was sequenced, but sequencing offers a unique opportunity to catch more of these risk factors early and identify individuals who may require more vigilant screening.
In the 1990s, scientists discovered that a particular pair of genes, which they named BRCA1 and BRCA2, were associated with a subset of breast cancer cases attributed to Hereditary Breast Ovarian Cancer Syndrome (HBOC—breast and ovarian cancer are often categorized together because they share similar risk factors). A mutation in either BRCA gene is associated with an increased risk of breast cancer (the standard risk is about 12% but with a BRCA mutation it can be as high as 87%), as well as an increased risk of other cancers including ovarian and prostate cancers.
HBOC only accounts for up to 10% of breast cancers and only 0.2% of the general population has a BRCA mutation. BRCA mutations are more prevalent in people with an Ashkenazi Jewish ethnic background, about 2.5% of people with Ashkenazi Jewish background have a mutation in one of these genes. In fact, while most people with a mutated BRCA have a completely unique mutation, people who have certain ethnic backgrounds (mainly Ashkenazi Jewish, as well as individuals from Sweden, Iceland, and the Netherlands) tend to have specific mutations that recur within their ethnic group. In genetics, this is called the founder’s effect, and it occurs in any small population that is genetically isolated from other populations for long periods of time. Specific mutations arise within the population and grow in prevalence rather than being bred out.
Genetic screening for BRCA1/2 mutations can help doctors determine an individual’s risk of developing breast cancer. Once an individual is identified as having a higher risk, their doctor can develop a personalized plan for screening and prevention. Additionally, there are some new drugs that have proven effective for breast cancer prevention or treatment in BRCA-positive individuals.
The BRCA1/2 genes are known as tumor suppressor genes, and their protein products are involved in the repair of Double-Strand Breaks in DNA, which are often carcinogenic if left unrepaired (I wrote more about DNA repair in the blog post on CRISPR and genetic engineering). It is easy to see how a mutation in an important DNA repair mechanism might be linked to an increased risk of cancer. There is a list of other heritable gene mutations that can increase breast cancer risk, mostly mutations of genes involved in DNA repair or the regulation of cellular replication. A BRCA screen may not catch all individuals with risk factors, so widely available genome sequencing could help catch some of the at-risk individuals who fall through the cracks.
When an individual is diagnosed with breast cancer, doctors often biopsy the tumor (take a small sample of tissue) to determine whether the cancer is human epidermal growth factor receptor 2 (HER2) positive. HER2 is a surface receptor protein involved in promoting cell growth, and when it is over-expressed in breast cancer tissue, it causes the cancer to grow and spread aggressively. If the tumor is positive for HER2, there are drug therapies that are targeted to that receptor.
Because HER2-positive breast cancer arises from overexpression of the HER2 gene, scientists have shown that introducing a HER2 mutation, through CRISPR-Cas9 targeted gene editing, results in a dominant negative mutation. This just means that instead of just producing less HER2 protein, the mutant gene produces a mutant protein that actually inhibits HER2’s cell growth function—if every HER2 molecule is a dedicated cellular construction worker helping to build a new cell brick by metaphorical brick, then mutant HER2 is actively interfering in that progress by removing the “bricks” or distracting HER2 with donuts.
In the future, CRISPR-based targeted breast cancer therapies could make the treatment of aggressive breast cancers more successful and less harmful to the patient. There is even the possibility that scientists could develop CRISPR-based methods to fix BRCA mutations and other breast cancer risk factors on the embryonic level. These sorts of personalized genetic strategies could revolutionize how we prevent and treat all sorts of cancers.
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