Genetic Sequencing May Identify Cancers Often Missed by Traditional Screening Guidelines

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Whole-exome sequencing of a large database identified carriers of mutations associated with hereditary cancer syndromes (ie, hereditary breast and ovarian cancers and Lynch syndrome). What was surprising was that among those carriers, about 40% did not satisfy the existing National Comprehensive Cancer Network (NCCN) criteria for screening and therefore would not have been identified as having these genetic syndromes. These findings of the TAPESTRY study were reported at the American Association for Cancer Research (AACR) Annual Meeting 2023.1

More than 44,000 patients treated at one of the three Mayo Clinic sites provided a saliva sample that was subjected to whole-exome sequencing. Among 550 carriers of pathogenic mutations in genes associated with both types of hereditary cancer, 52.1% did not know before the study that they had a cancer predisposition condition, and 39.1% did not satisfy the existing NCCN criteria for genetic study. Further, among newly diagnosed patients with hereditary breast and ovarian cancers or Lynch syndrome during the study, 60% were not eligible for genetic screening per the current guidelines.

“The knowledge that comes from genetics can empower patients to take control of their disease risk and increase the likelihood of avoiding a deadly cancer diagnosis or catching it at an early stage when it is highly curable. This study shows the feasibility of providing whole-exome sequencing to large populations of patients within an integrated health system and diagnosing individuals who have an inherited susceptibility to cancer,” stated N. Jewel Samadder, MD, Professor of Medicine at the Mayo Clinic College of Medicine, and Co-Leader of the Precision Oncology Program at the Mayo Clinic Comprehensive Cancer Center.

N. Jewel Samadder, MD

N. Jewel Samadder, MD

If people know they have a genetic risk for certain cancers, they can undergo screening and consider preventive strategies. For patients with hereditary breast and ovarian cancers, this may include advanced breast imaging and prophylactic mastectomy and/or oophorectomy. For patients with Lynch syndrome, this may include regular colonoscopies, blood and urine screening, and prophylactic hysterectomy.

Regarding the NCCN criteria, Dr. Samadder stated: “These criteria were created at a time when genetic testing was cost-prohibitive and thus aimed to identify those at greatest chance of being a mutation carrier in the absence of population-wide whole-exome sequencing. However, these conditions are poorly identified in clinical practice, and many patients are not aware of their cancer risk.”

Whole-exome sequencing has become less expensive and more widely accessible. Now, it can be done on a saliva test for as little as $500 per test.

Guidelines or Lack of Family History?

“The findings from the TAPESTRY study are not new. They are consistent with other studies with a large clinic-based biobase. Multiple studies have shown the same thing; if you take a large population and study it with sequencing—either whole-exome sequencing or sequencing for particular genes of interest for hereditary cancers—you will find a positivity rate of about 1.2% for previously unrecognized mutations associated with hereditary cancer. These studies are based on medical records,” said Katherine Nathanson, MD, Director of Genetics for the Basser Center for BRCA, Abramson Cancer Center of the University of Pennsylvania.

Katherine Nathanson, MD

Katherine Nathanson, MD

“For me, this study reinforces the importance of taking a good family history. Many of these people might have been identified if a thorough family history were taken. It also reinforces the importance of ‘cascade testing’—that is, referring family members of a carrier for genetic testing. One possibility is to use an automated system to identify people through electronic medical records who should be tested but have not been tested,” Dr. Nathanson suggested.

Regarding the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), at least for screening for breast cancer, Dr. Nathanson said they are quite “broad and generous.”

“There are people who argue for a ‘genome-first’ approach. I think it is not cost-effective, and it is logistically complicated to do whole-exome sequencing or genetic testing on everyone. We don’t have an educated work force on genetics and genomics,” she continued.

“It may not be that the NCCN Guidelines per se should be revised, but rather how they are implemented. Health-care providers and patients need to be aware of the importance of taking a good family history, so they can identify people who are candidates for genetic screening. The public also needs to be aware of criteria for screening,” she added.

Study Details

The TAPESTRY study performed whole-exome sequencing on saliva samples provided by 44,306 patients receiving care at any of the three Mayo Clinic sites (Arizona, Florida, or Minnesota). For the data reported at the AACR Annual Meeting, samples were tested for pathogenic mutations in BRCA1 and BRCA2 (for breast and ovarian cancers) and MLH1, MSH2, MSH6, PMS2, and EPCAM (for Lynch syndrome). The researchers also reviewed the electronic health records of patients with these diseases for demographics, personal history of cancer, and satisfaction of NCCN criteria for genetic evaluation and testing.

They identified 550 carriers of either hereditary breast and ovarian cancers or Lynch syndrome, for a 1.24% prevalence for these two autosomal-dominant precursor cancers. The sample was about 90% White, with a median patient age of 57 years. About 45% had a personal history of cancer. About half of all the cases were “new” diagnoses.

About 50% of those with a new diagnosis of hereditary breast and ovarian cancers (n = 190) and 60% of these with newly diagnosed Lynch syndrome (n = 96) had no prior knowledge of their genetic predisposition. In regard to individual mutations, the largest group with a new diagnosis with no prior knowledge of their predisposition were carriers of PMS2 (82%).

A deeper dive into the data showed that about 40% of patients diagnosed with these cancers did not meet the NCCN Guidelines criteria for genetic screening (32% of the hereditary breast and ovarian cancers group and 56% of those diagnosed with Lynch syndrome). For individual genes, 83.7% of those identified with PMS2 did not meet NCCN criteria for genetic evaluation. “These guidelines are used by insurers to pay for testing,” Dr. Samadder told listeners.

Among the patients who did not meet NCCN criteria for genetic evaluation and testing, 63.3% had no personal history of cancer, 60.5% had an insufficient number of relatives with cancer, and 58.6% had a type of cancer unrelated to genetic syndromes.

Dr. Samadder and coauthors also found that minority patients fared even worse. About 50% of minority patients who were carriers of these genes did not meet the NCCN criteria vs 39.2% of White patients.

He also noted that 34% of patients who met the criteria in the NCCN Guidelines had not been tested clinically, showing “the guidelines are not being appropriately used.”

“Our results emphasize the need for increased access to genomic screening for hereditary breast and ovarian cancers and Lynch syndromes, and the potential use of whole-exome sequencing in large populations,” he stated. 

DISCLOSURE: Dr. Samadder has served as an independent contractor for One Two Therapeutics, Janssen Research and Development, Guardant, Tempest, and Recursion Pharmaceuticals. Dr. Nathanson reported no conflicts of interest.


1. Gay E, Samadder NJ, Bublitz ML, et al: Genetic screening in a tertiary medical center identifies carriers of cancer predisposition diseases that would be missed by clinical guidelines. AACR Annual Meeting 2023. Abstract 5768. Presented April 18, 2023.