by IPM staff
A new study from the Mayo Clinic finds that current screening protocols fail to catch a significant number of individuals with genetic mutations linked to hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome, which increase the risk of developing certain cancers. Their findings, published in JCO Precision Oncology, finds that the rate of mutations is higher in underrepresented minorities than is currently assumed with current screening guidelines.
The paper is the first to be published from the Tapestry study which has enrolled more than 100,000 patients seeking care at geographically and racially diverse Mayo Clinic facilities in Arizona, Florida, and Minnesota. The study aims to investigate how exome sequencing could influence healthcare outcomes, starting with hereditary cancer syndromes and cardiovascular conditions.
In their study of the first 44,000 Tapestry enrollees, the team chose to focus on several CDC tier one genes. These genes are associated with Lynch syndrome (hereditary colorectal and gynecological malignancies), and BRCA1 and BRCA2 (breast and ovarian cancer).
“This is the first comprehensive data on the population frequency of these genetic disorders in large, unbiased sequence groups,” says lead author Niloy Jewel Samadder, MD.
These genes were chosen based on substantial evidence indicating that mutations in these genes significantly increase the risk of cancer, cardiovascular disease, and mortality. Moreover, effective preventive measures are available for these conditions.
One of the key findings of the study was the prevalence of hereditary cancer syndromes within the patient population. Out of the 44,306 patients analyzed, 550 were found to carry mutations in one of the seven tier-one genes analyzed. This translates to approximately 1.24% of the Mayo Clinic population having a hereditary predisposition to cancer. In practice, of those 550 individuals, nearly 40 percent of them would not have qualified for cancer risk testing under current National Comprehensive Cancer Network (NCCN) guidelines.
Of the 550 individuals, 27.2% had BRCA1 mutations, and 42.8% had BRCA2 mutations. Lynch syndrome mutations were found at the rate of 12.3% for MSH6, 8.8% for PMS2, 4.5% for MLH1, 3.8% for MSH2, and 0.2% for EPCAM. Broken down by genes, the researchers found that 63.8% of people with MSH6mutations would not have met NCCN screening criteria. The same was true for 83.7% of those with PMS2 variants.
Further, half of the patients with these genetic mutations were unaware of their condition. “Even at an academic medical center, we found that around half of the patients had a new diagnosis of these genetic conditions,” says Samadder. “The rate of new diagnoses would likely be higher in community settings without specialized genetics or cancer care.”
He and colleagues believe the result of their analysis revealed significant limitations in the current genetic testing guidelines set by the NCCN. These guidelines play a crucial role in determining insurance coverage for genetic testing based on a patient’s personal and family history of cancer.
However, in this study, 49 percent of participants from underrepresented minorities whose whole-exome sequencing tests identified Lynch syndrome or HBOC wouldn’t have met the NCCN criteria for testing, whereas the same was true for just 32 percent of white individuals.
The top reasons for falling outside the testing guidelines included a lack of personal cancer history, an insufficient number of relatives with cancer history, or a personal or family history of a cancer type not related to the genetic syndrome. Samadder pointed out, “This miss rate was notably higher for minority patients, indicating that the guidelines are biased towards European populations.”
Now that the Tapestry study has enrolled its total cohort, the team plans to redo their analysis. “I don’t think it will change the larger findings but just give us more robust results,” Samadder adds. “We are now at 550 individual mutation carriers, but it is probably going to be closer to 700 or 800.”
The authors believe the study has two important implications. The first is the need to update and refine the NCCN guidelines to be more inclusive and reflective of diverse populations. As Samadder highlighted, “We need to move towards a more inclusive approach in genetic testing guidelines, ensuring that minority populations are adequately represented and not overlooked.”
Second, the study adds to the body of knowledge supporting routine genomic sequencing, particularly for cancer patients. “The ease and affordability of sequencing have improved dramatically,” says Samadder. “Sequencing can now be done on a saliva sample mailed from home, costing less than a Netflix subscription.”
Samadder specifically suggests that genomic sequencing for CDC tier one genes should be routinely offered to individuals at age 40, citing a 2023 study in the Annals of Internal Medicine that demonstrated sequencing costs are now low enough to justify widespread testing.
“Exome sequencing for CDC tier one genes is probably sitting at around $500 today,” he says, “so we are at that cost-effectiveness pivot point where the cost of sequencing justifies routine testing, which can lead to early detection and preventive measures for hereditary conditions. We are on the brink of making genomic sequencing a standard practice for all cancer patients.”
This article was published by: Inside Precision Medicine