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Since 1989 hundreds of wrongly convicted prisoners have been exonerated thanks to a technology known as polymerase chain reaction (PCR). Developed in the 1980s, this Nobel-Prize-winning technology allows scientists to make millions of copies of DNA from trace samples of saliva, blood, hair, or any other genetic material, giving investigators the opportunity to replicate enough DNA to perform a thorough genetic analysis. As a result, many prisoners who had been convicted of murder, rape, and other crimes were found to be innocent when their DNA did not match what was found at the scene. Thanks to science, some these innocent people were finally able to walk free.
Wrongful identification isn’t just a problem in criminal justice, however; it’s also a problem in medicine. Sometimes, in an effort to identify or define a genetic syndrome, genetic testing can point to the wrong “convicted” gene, resulting in a patient being told they carry a gene for a specific cancer syndrome when they don’t. When this happens, patients are often told to undergo intense screening and/or preventative surgeries to minimize their risk of developing a disease that, in reality, they harbor a low risk of getting. Fortunately, just as advances in DNA testing have led to the exoneration of wrongly convicted prisoners, new genetic testing technology is freeing some people of the harm that comes with an incorrect genetic diagnosis.
Take cancer. In 2016, more than one million people in the United States were diagnosed with cancer. Cancer is so common that most families have at least one member who has faced or is currently facing it. Cancer is caused by genetic mutations, which may be hereditary or not. Inherited mutations—otherwise known as “germline” mutations—cause a significant number of cancer cases. However, the vast majority of cancers are caused by somatic mutations, which result from environmental factors like aging, smoking, or other things that cause wear and tear on our DNA.
While the result of these mutations are essentially the same (i.e. the patient develops cancer), the implications of a hereditary mutation are far greater because it means patients and their families may be at risk for developing more cancers. Fortunately, thanks to a new test that pairs traditional blood testing with tumor testing, scientists now have a way to determine whether a mutation is germline or somatic, giving patients and their families a better chance of a correct diagnosis.
This new test has changed how we approach genetic testing, especially when it comes to Lynch Syndrome, the most common hereditary cancer syndrome. Lynch Syndrome is found in one out of every 350 people and is caused by a single inherited mutation in one of five genes. It increases the risk of many types of cancer, including colon, uterine, ovarian, and other GI-tract cancers, so people with Lynch Syndrome are advised to undergo intensive screening regimens and surgeries to prevent cancer from developing.
Traditionally, when someone is diagnosed with colon cancer, their colon tumor is removed and sent to a molecular pathology lab for additional studies. One of the tests the lab may perform checks to see if certain proteins can be found in the colon tumor. Our genes provide the instructions for making a protein, which carries out a specific job in our body. Therefore, if a protein is not found in the tumor, it may mean that the instructions or gene for making the protein are “broken” or mutated.
Commonly, the molecular pathology lab looks for clues in the tumor that might suggest an individual has Lynch syndrome. If the colon tumor is missing certain proteins, the case is flagged for follow-up and referred to the cancer genetics clinic to determine if the patient has Lynch syndrome. Cancer geneticists determine whether someone has Lynch syndrome by performing a blood test to see if they have an inherited mutation in one of the five genes that are known to cause Lynch syndrome. But what does it mean if we can’t find an underlying inherited mutation? Does this mean they don’t have Lynch syndrome?
Unfortunately, we don’t know enough about our genome to answer that question. We have come a long way, but there are still genes and mutations that we can’t detect with our current technology. Just because we did not find an inherited gene mutation for Lynch syndrome does not mean the patient doesn’t have Lynch syndrome.
In the past, cases like this—in which the colon tumor was flagged as suspicious but blood testing did not reveal an inherited mutation—were classified as “uninformative” Lynch syndrome. With a diagnosis of “uninformative” Lynch syndrome, doctors recommended the patient and all of their first-degree relatives (siblings, children, and parents) consider following the rigorous Lynch syndrome management guidelines, which involve yearly colonoscopies and possibly the surgical removal of the uterus, tubes, and ovaries. Just think about how much unnecessary screenings, surgeries, and health care costs we could avoid if only we knew for sure whether the patient had Lynch syndrome.
Thankfully, we now have new tools and tests available to help get answers for some of these complex cases. For example, the commercial testing laboratory Ambry Genetics offers a test called TumorNext, which, in addition to looking for inherited mutations for Lynch syndrome using a blood or saliva sample, also analyzes the colon tumor for somatic mutations. This is much simpler and more informative than testing the tumor for missing proteins.
Take Jason. Jason came to our clinic after being diagnosed with colon cancer in his 40s. He’d been told he may have Lynch syndrome because molecular pathology of his colon tumor had shown certain proteins were missing. Notably, Jason had no family history of a Lynch-type syndrome—nor did he have related cancers, and testing Jason’s blood did not identify an inherited gene mutation. Prior to our ability to do TumorNext testing, Jason would have been diagnosed with “uninformative” Lynch syndrome and been stuck with a lifetime of intensive screening. In addition, all his children and siblings would have been told to follow Lynch syndrome management guidelines. Thankfully the TumorNext test allowed us to analyze Jason’s tumor for tumor-acquired mutations that could provide a definitive answer.
Indeed, Jason’s tumor showed mutations in multiple genes whose proteins had gone missing. Since these mutations were found only in the tumor and not in his blood, we know they are somatic rather than inherited. This means Jason doesn’t have a hereditary cancer due to Lynch Syndrome, but rather a non-hereditary cancer.
So, just as DNA testing has exonerated several wrongly convicted individuals in prison, TumorNext has freed Jason and his family from a diagnosis of “uninformative” Lynch syndrome and a lifetime of high-risk screening. In upcoming years this kind of tumor testing will be performed more and more, and not just for colon cancer patients but for other patients as well. The comparison of tumor and blood genetics will help us discover new cancer genes and define if and when they were broken—at birth or during life. Soon we hope to be able to provide all cancer patients with such tests.
Note: This piece was co-written with Amber P. Gemmell MS CGC, Cancer Genetics Program, UT Southwestern Medical Center.
