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Genomic Testing: The Risk of Knowing Too Much

Sophisticated tests can generate a wealth of information about a patient’s cancer or disease risk. 
But they also raise serious questions. By Alexandra Goho

​Consider the following: A healthy woman in her early 20s has a family history of breast cancer. She decides to undergo genetic testing to determine her own breast cancer risk. But instead of simply testing for the BRCA1 and BRCA2 gene mutations, her doctor offers her a new kind of test that looks at more than a dozen genes associated with a wide range of tumor types. The results come back. The good news is she doesn’t have any mutations in the two breast cancer genes. The bad news is she has a mutation in a gene called TP53 that is associated with a rare disorder called Li-Fraumeni syndrome (LFS). Women with the inherited disorder have more than a 90 percent chance of developing some kind of cancer—breast cancer, brain cancer, sarcoma, leukemia or another cancer type—during their lifetime.


Questions to Ask Your Doctor
Learn more about genetic testing before you're tested.

Understanding Genomic Testing
Learn more about genomic testing in this web-exclusive interview with cancer geneticist Kenneth Offit.

Kenneth Offit, a cancer geneticist and medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, has seen two cases like this in his clinic. Explaining these kinds of test results to patients is not easy, he says. Although patients with LFS can undergo intensive screening with regular blood tests, MRIs and physical examinations, determining the best screening methods can be a challenge because of the wide range of tumors that can develop. What’s more, there are no treatments for LFS.

While genetic testing for inherited cancer mutations has become more common as an increasing number of people seek to understand their cancer risk, advances in genome sequencing—the process of determining the precise order of the four chemical bases A, T, C and G that make up a person’s DNA—have taken testing to a new level. Instead of testing just one or two genes, companies now offer gene panels that analyze dozens of cancer-related genes simultaneously from a single patient sample. Some tests sequence hundreds of genes, and even entire genomes. The hope is that more comprehensive genomic testing will lead to a more precise understanding of a person’s cancer risk, allowing patients to take preventive measures like routine screening or prophylactic surgery to protect themselves. The additional genetic knowledge could also help protect their family members.

But sequencing that much DNA presents oncologists and patients with a conundrum: The tests generate an enormous amount of information, some of which isn’t yet clearly understood. And even if the findings are understood, they can blindside a person by uncovering an unexpected disease risk or discovering a cancer-associated mutation for which there are no preventive measures or treatments.

“It’s really important for people to know what they’re getting into when they undergo testing with these multigene panels,” says Susan Domchek, a medical oncologist at the University of Pennsylvania’s Abramson Cancer Center in Philadelphia. “They need to talk to their doctor about the pros and cons, because I think there is the assumption that more is better. But like everything, that’s not always true.”
Multigene Panel Testing on the Rise
More than a half dozen major commercial laboratories provide multigene cancer panel tests. Ambry Genetics offers a test called CancerNext that looks at 28 genes associated with breast, ovarian, colorectal, uterine and several other cancers. Myriad Genetics offers Myriad myRisk, a test that looks at 25 different genes and identifies mutations associated with an increased risk for eight types of cancer. “Gene panels are essentially replacing single gene testing,” says Offit, who anticipates that soon physicians will be unable to order some single gene tests from large commercial companies.

The reasons are partly economic. It’s cheaper and more efficient to test multiple genes at once than to test those same genes one by one in individual tests. It can also be easier on patients. For example, if a person with a family history of melanoma and pancreatic cancer tests negative for a CDKN2A gene mutation associated with a high risk of these cancers, it can be reassuring. But a doctor trying to understand the reason for the family history may order more genetic tests to look for other mutations that predispose to these cancers.

“That means more visits to the clinic, more waiting for test results, more time off work,” says oncologist and cancer geneticist Theodora Ross of the University of Texas Southwestern Medical Center in Dallas. “So there are a lot of reasons to do a panel up front.”

On the other hand, because some multigene panels cover a wide range of cancers, people may not be prepared to deal with all of a test’s findings. A patient might have a panel test to determine her risk of ovarian cancer and instead discover she has a mutation in a gene called CDH1, associated with a very high risk of developing stomach cancer. Such instances are rare but have big consequences. Doctors routinely recommend that patients with this mutation have their stomachs removed as a preventive measure.
“That is a huge deal and has major issues about quality of life,” says Domchek. And although patients can choose not to receive certain findings, they need to be aware of the consequences of not knowing that information, says Offit, such as the effect on relatives who might want to be warned of an inherited mutation or the impact on any future children.


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