ON Aug. 6, researchers announced in The New England Journal of Medicine that they had found that mutations in a gene called PALB2 greatly increase the risk of breast cancer. This is one of the biggest developments since the discovery in the ’90s of the role of mutations in the BRCA1 and BRCA2 genes in breast and ovarian cancer.
The response among patients has been predictable. One woman’s email to me summed it up: “I’d like to get an entire genome scan to rule out a hiddencancer diagnosis.”
Genetic testing has revolutionized how we think about cancer, allowing us to make some decent predictions about who might get certain cancers and who might benefit from preventive treatments. Many know the story of Angelina Jolie, who used her family history to learn she had a BRCA1 mutation. She chose to have a double mastectomy instead of waiting to see if she developed cancer. We may not envy this choice, but we do appreciate the power that comes with taking evidence-based action against a deadly disease. Many of us want that power for ourselves.
The problem is that many patients think genetic testing can tell us far more than it does. Despite the exaggerated claims of some entrepreneurs and lab owners, we can’t predict patients’ cancer risk and advise them appropriately just by sequencing their genome. At least not yet.
First, it’s important to know the difference between sequencing a tumor and sequencing a germ line (which is what the woman who emailed me wanted).
The germ line genome is found in every cell of the body and encodes traits such as eye color and the tendency to develop diseases like cystic fibrosis. It is the blueprint you inherited from your parents.
The tumor genome is like an ugly addition on top of the original construction. It’s acquired rather than inherited, and contains a mess of new mutations, a subset of which cause the cells to proliferate out of control and transform into cancer.
Sequencing a portion of a tumor genome can sometimes tell us what went wrong and how the cancer might be treated more effectively. For instance, testing people with melanomas for mutations in their BRAF genes can influence treatment. But it’s unclear how many people would benefit from sequencing all the genes in a tumor; it, like full germ line sequencing, remains mainly a research tool.
Both tumor and full germ line sequencing suffer from the same problem: The whole genome doesn’t make a lot of sense to us yet. We have a very limited understanding of which variations in DNA contribute to disease development. Most of your genome sequence looks the way Shakespeare does to a toddler — incomprehensible.
Conscientious doctors won’t order a lab test that they can’t understand, so they’re unlikely to say yes to a patient’s request for full genome sequencing. And insurance companies shouldn’t pay for a test if there isn’t research backing up its use.
The genetic tests that are clearly valuable at this point for predicting cancer risk are those for the specific mutations that we understand. But even then there can be other mutations in the same genes that are of unknown clinical significance. So the best results come from sequencing the subset of genes that could potentially explain patterns of disease observed in the family tree. If your family shows an increased incidence of certain cancers, it makes sense to look for known mutations that increase the risk of those cancers.
For example, we recently saw a 25-year-old patient at our clinic with a strong family history of colon cancer. His father had colon cancer, but had refused any kind of genetic testing. When the son tested positive for a broken colon cancer gene, the rest of his family followed. Those who tested positive now know they need to have frequent colonoscopies. And most people with strong family histories of breast cancer should consider getting genetic counseling and, if recommended, testing for mutations in genes such as PALB2, BRCA1 and BRCA2.
Family history doesn’t just help us decide where to look for broken genes; if we find a mutation that could lead to cancer, the number of cancers in the family helps us determine what kind of risk that mutation might carry. Some patients with BRCA mutations have a 40 percent chance of developing breast cancer by age 70, but for others, the chance has been estimated to be as high as 87 percent. It looks as if this is the case for PALB2 mutations as well. According to the New England Journal of Medicine study, by Marc Tischkowitz at the University of Cambridge and others, patients with a broken PALB2 gene and no family history of breast cancer have a 35 percent chance of developing breast cancer, but if they had two or more family members with cancer, the risk rises to 58 percent. This is significant when you’re considering life-altering preventive surgery or screenings.
Genetic testing is a process for many patients, not a one-time event. In the coming weeks, in light of the report on PALB2, as well as the emergence of sophisticated tests that can now analyze many cancer genes at one time, we’ll advise former patients who tested negative for the BRCA or other specific genes to return for more genetic counseling and potentially further testing.
One patient, who is now healthy but who dealt with a breast cancer diagnosis in her early 30s, emailed to ask if she’d been tested for the PALB2 gene when she had the BRCA test in 2007. We’d found no mutations, and she seemed to be a genetic mystery. My reply was easy: She hadn’t been tested for PALB2, but she should be now, along with any other new cancer genes. If she tests positive, we’ll know more about the risk of her having a second cancer, and be able to test her family members.
For any patient who still wants to get his or her full genome sequenced, there is one good reason to do it: scientific curiosity. Something of interest could come of it as the technology improves over time. But it’s worth doing only if a clinical trial is paying for it, or if you can easily afford it. Getting the data can cost under $2,000, but having the data interpreted can cost in the tens or hundreds of thousands. It’s a fine purchase, but definitely a luxury. And bear in mind that the data that come back will raise more questions than they answer. There is a good chance that mutations of unknown clinical significance will be found that will increase anxiety without illuminating any known risks.
We have to have patience with the pace of research. We can now use genetic information to prevent breast, ovarian and colon cancer in many patients, and we will get better at this. In the meantime, most people should focus less on the high-tech future of genetic testing and more on the low-tech history of their family trees. Those who don’t know their own family histories, because of adoption, secrecy, loss or estrangement, should take comfort in the fact that we are one big family. Data in aggregate from many families,gathered together in studies like Dr. Tischkowitz’s, will eventually teach us how to manage our risks, how to treat disease and how to save lives.