Guideline Testing Can Miss Genetic Mutations, Study Finds


Standard guidelines that determine who should undergo genetic testing may result in some cases falling through the cracks, according to recent research.

 Niloy Jewel Samadder, MD

Niloy Jewel Samadder, MD

While genetic testing lays the groundwork for individualized cancer care and better outcomes, many patients are having their targetable mutations missed, according to recent research published in JAMA Oncology.

Researchers analyzed 2984 genetic testing results from patients with cancer who were treated at one of the Mayo Clinic Cancer Center’s 3 locations: Arizona, Florida, and Minnesota. Findings showed that 13.3% (397) patients had a pathogenic germline variant (PGV) that was associated with the development of cancer.

There were 27 patients who had more than 1 PGV, and 2 patients had 3. When stratified by risk posed by PGV, 149 patients were at high risk; 133 were at moderate; 65 were at low; and 50 patients were carriers of variants that were associated with recessive syndromes.

"We found that 13.5% of patients had an inherited mutation in a gene associated with the development of their cancer," said study author Niloy Jewel Samadder, MD, a Mayo Clinic gastroenterologist and hepatologist, in a statement.

"Everyone has some risk of developing cancer, and in most cases the disease develops by chance. However, some people are genetically predisposed to developing certain types of cancer, such as breast or colon cancers."

However, less than half (48.4%) of the inherited mutations would have been caught with standard guidelines determining who should get genetic testing. These guidelines include those that were established by the National Comprehensive Cancer Network (NCCN), the National Society of Genetic Counselors (NSGC), and the American College of Medical Genetics (ACMG).

Finding these genetic mutations could be crucial in determining what kind of therapy an individual gets. In fact, 28% of patients with high-penetrance PGVs had their treatment changed as a result of the findings.

“A striking result was that nearly 1 in 3 identified PGVs would not have been detected using the 2018 or 2020 NCCN guidelines, including identification of 124 high- or moderate-penetrance PGVs,” the authors wrote. “This finding highlights the limitations of clinical and guideline-backed risk assessment and is consistent with what other studies have reported.”

In addition to potential treatment changes, the authors also explained that it is important for patients to know if they have a genetic mutation so that they can share the information with their family members, too. Though the researchers also recognized that outside of a clinical trial, families may face barriers when it comes to cost or communication.

“Equally important to the discovers of PGVs in a patient with cancer is the potential to share these findings with their relatives, allowing for earlier disease detection and cancer prevention,” they wrote.

“In our study, the traditional barrier of cost was removed, and efforts were made to ensure accurate communication of the results to family members with a letter and an easily accessible video that explained the benefits and limitations of genetic testing.”

Ultimately, the study highlighted the benefit of multigene panel testing, which led to the discovery of more cancer-related genetic mutations than currently published guidelines.

“This study offers significant insight into the performance of multigene panel testing and has broad implications for its wide clinical implementation and acceptance in oncology practice,” the authors wrote.

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