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DTC genetic testing: Increased uptake requires expert guidance
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In this guest commentary from the steering committee for the Collaborative Group of the Americas on Inherited Gastrointestinal Cancers (CGA-IGC), Michael Hall, MD, of Fox Chase Cancer Center, Matthew Yurgelun, MD, of the Dana-Farber Cancer Institute, Swati Patel, MD, of the University of Colorado, and Heather Hampel, MS, LGC, of the Ohio State University Medical Center, address the need for greater physician awareness amidst the growing uptake of direct-to-consumer genetic testing that may or may not indicate an increased risk for certain gastrointestinal and other cancers. CGA-IGC is a clinical research group focused on hereditary GI cancers. It supports greater access to genetic testing, but with guidelines and research necessary to comprehend the downstream impact.
There are many factors that contribute to why people develop various diseases, including cancer. In addition to environmental factors and health behaviors, genetic predisposition is a well-established risk factor for cancer. Recent data suggest that regardless of family history or age of diagnosis, up to 10% of certain cancers have underlying genetic predisposition identifiable with current genetic testing technology.
Patients with cancer often seek care of professionals such as oncologists, surgeons, gastroenterologists and genetics experts to determine if there might be a genetic predisposition to the cancer that they’ve developed. Additionally, patients with a family history of cancer are often evaluated by a genetics expert to determine if there might be something hereditary within the family.
The tide of genetic testing recently shifted from fully entrenched within the health care system to what could be called “recreational genomics” in which people seek genetic ancestry information or genetic health information via direct-to-consumer (DTC) tests. For example, 23andMe recently received FDA approval to test for specific alterations in the MUTYH gene (which can cause MUTYH-Associated Polyposis [MAP]) and previously received approval to test for three specific gBRCA mutations.
In this commentary, we want to clarify the difference between mixing diagnostic genetic testing for known hereditary adult cancer syndromes with non-diagnostic polymorphism-based testing looking at associations of different markers for physical traits or ancestral origins. Even to seasoned physicians, it may not be clear that this kind of genetic testing is wholly different and, without guidance, can lead to misconstrued results.
Removing barriers
It is understandable that there has been a huge surge in demand for DTC genetic testing. Though it began as a novelty to learn about ancestry, DTC is now increasingly trying to address existing barriers to people obtaining professional genetic advice, testing and access to genetic counselors. The problem arises when they blur this novelty with health information.
We applaud these companies for bringing genetics to the public and increasing awareness of the hereditary predisposition to various diseases. With that said, the approach to clinical genetics is nuanced and complicated, all the way from selection of which genes to evaluate to interpretation of results and generating clinical recommendations.
It is important to proceed with caution and ensure that the correct testing is chosen, and it is correctly interpreted.
We commend the FDA for recognizing the limitations associated with the recently approved DTC testing. The FDA emphasizes that these DTC tests should not be used for medical treatment without consulting a medical professional. Unfortunately, sometimes that message doesn’t make it to the patient or their physician. A patient should seek counseling from a genetics expert to ensure DTC results are accurately interpreted and verified, if need be.
We are strong believers that genetic testing for inherited cancer risk is an incredibly powerful tool to help prevent cancer, but at the same time not all testing and test interpretation is created equal. It is important to confirm that patients are getting appropriate testing, accurate test interpretation and guideline-based clinical recommendations to reap the cancer risk-reduction benefits and ensure they are not undergoing unnecessary, potentially risky, medical interventions. We in the genetics community also need to do a better job of making these tests and expertise accessible on people’s own terms. We may need to learn from the DTC companies how to increase access to quality information.
Pre-testing
For patients interested in genetic testing or for physicians considering referring their patient for genetic counseling, it’s important to understand what the DTC testing companies offer in contrast to clinical testing.
For instance, for a patient who has a strong family history of cancer or who has developed cancer themselves, it’s appropriate to consider whether they should undergo genetic testing.
What’s important to understand is the testing offered by DTC companies is very narrow. For BRCA, 23andMe only tests for three mutations specific to individuals with Ashkenazi Jewish ancestry. That is three out of the thousands of mutations known to cause hereditary breast and ovarian cancer syndrome. The MUTYH 23andMe test only includes two out of the thousands of mutations in only one out of dozens of genes described to contribute to colorectal cancer risk.
To make it simple, in any medical context where a physician would consider testing for the mutations on a 23andMe panel, this testing is insufficient to fully evaluate breast cancer risk and this testing is insufficient to fully evaluate colorectal cancer risk. These cherry-picked sites from hereditary breast and colon genes are valid tests, but for a very limited piece of information. In fact, it is quite possible a patient could receive information that the BRCA testing or MUTYH testing on 23andMe was negative, yet they could still in fact have high risk mutations associated with these genes that simply were not tested.
The decision to refer a patient for genetic evaluation is very important. Patients interested in learning more about their predisposition to cancer should be seen by a clinical professional who can evaluate all the potential genetic predispositions rather than just the handful of sites in very complex genes.
A clinical evaluation includes acquisition of detailed personal and family history, including any prior genetic testing in the patient or their family. Based on this information, genetics experts formulate a comprehensive genetic risk assessment, discuss the options for genetic testing, what information is expected to be gained and potential limitations to testing. Based on this discussion, a shared decision is made between the genetics expert and the patient about how best to proceed with genetic testing. DTC testing increases access to very limited cancer genetics testing and leaves patients with the potential for confusion in test interpretation.
Ripe for misinterpretation
Once a patient has undergone genetic testing, accurate result interpretation is critical.
Our biggest fears with the new additions to 23andMe are twofold: under-treatment or over-treatment.
If a patient goes through 23andme and walks into the office with these results, call or consult a genetic counselor to be sure you and the patient are interpreting these results correctly. It’s a great time to phone-a-friend and ensure we are living up to “do no harm.”
Additionally, conditions are inherited in different ways.
Inheriting one abnormal copy of a BRCA gene can significantly increase the risk of breast, ovarian, prostate and pancreatic cancer. We fear patients who seek this testing out based a personal or family history of breast or ovarian cancer and get a “negative” result (ie, none of the three mutations checked) interpret this as having no hereditary predisposition. This is not only inaccurate because thousands of the known BRCA mutations were not even evaluated, but also because there are other genes that can increase risk for these cancers.
If this patient were to see a genetics expert, these limitations could be discussed and more broad testing offered.
Similarly, patients with multiple colorectal cancers in the family should understand current 23andme testing does not evaluate for the most common hereditary GI cancer condition (Lynch syndrome) and that a “negative” test for MUTYH mutations does not preclude the presence of another hereditary GI cancer mutation.
MAP mutations are also inherited in an autosomal recessive fashion. It requires inheritance of an abnormal copy from the mother and the father to have the clinical diagnosis and increased risk for polyps and cancer. Just having one abnormal copy of MUTYH does not cause MAP and does not significantly increase the risk for cancer (some data have suggested a very slightly increased risk for colorectal cancer, but this is not yet firmly established).
Individuals with single MUTYH mutations are quite common, but there are subtleties to the interpretation. If a patient receives a result that shows that they have one MUTYH mutation, they are merely a carrier, which up to 1% to 2% of people with northern European ancestry are. To have MAP and the associated markedly increased risk for colorectal cancer, one needs to have inherited two MUTYH mutations, one from each parent. Given how common these mutations are and some confusion about the inheritance pattern, there is a high likelihood that some carriers of a single MUTYH mutation will overestimate their risk for developing colorectal polyps and cancer. Conversely, since the 23andMe testing only includes two specific MUTYH mutations, this means that some individuals who are found to have one or none of these two MUTYH mutations, may still have MUYTH-associated polyposis because they have two different mutations in their MUTYH genes that were not included in the 23andMe test.
These nuances increase the chance of misinterpretation and could result in overtreatment. We worry that the nuance of carrier vs. biallelic mutations, which result in the disease state, may not be fully appreciated by patients or their medical providers. We worry that these patients may be exposed unnecessarily to invasive procedures such as colonoscopy or even colectomy.
Having some degree of involvement from a genetic professional is critical. You need a skilled clinician to help interpret and guide these results.
Take Home Messages
Genetic testing for hereditary syndromes is not black and white; the results are much more nuanced than positive vs. negative. These nuances of genetics – and there are many – undoubtedly get lost quickly. Many physicians themselves do not understand the intricacies.
DTC genetic testing removes that clinical hierarchy, taking the genetics experts’ input out of the equation. Patients can seek out genetic testing without the counseling from genetic experts and, more importantly, the necessary context. That context offers, up front, the selection of which genetic test is appropriate and, in the end, interpretation by a trained genetics expert as to what the results convey as far as risk.
People are often tested for a slew of genes at once and, with DTC testing, you get a very basic report. Without interpretation and guidance, there can be implications for people being falsely reassured or unnecessarily panicked or, in some cases, both.
Genetic counseling is still considered the standard of care when conducting diagnostic genetic testing. That is the gold standard and to not offer that in this setting is a deviation from that standard of care.
Resources
The National Society for Genetic Counselors (NSGC) is a great resource for patients and physicians in need of consults. Through the NSGC (www.findageneticcounselor.com), you can find experts in all 50 states. There are counselors who provide remote telehealth genetic counseling and reputable genetic counseling companies certified nationally to provide telephone genetic counseling.
There are many different resources available if you don’t have someone in your speed dial.
For more information: To learn more about the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer, visit http://www.cgaicc.com/.
Disclosures: Hall, Hampel, Patel and Yurgelun report no relevant financial disclosures.