Study Shows Feasibility of Using Exome Sequencing to Conduct CDCT1 Genetic Condition Screening


Whole-exome sequencing demonstrated the ability to identify genetic conditions in patients for whom clinical guidelines did not require testing.

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Whole exome sequencing has been deemed a potential method to help execute CDCT1 genetic condition screening on large populations, according to study findings presented during the American Association for Cancer Research (AACR) Annual Meeting 2023.

The findings, which were presented by Niloy (Jewel) Samadder, MD, demonstrated that in a cohort comprised of a large clinic population (n = 44,306), exome sequencing successfully identified Lynch syndrome (LS)/hereditary breast and ovarian cancer (HBOC), which include BRCA1 and BRCA2,in 1.2% of patients (n = 550). More than half of these were considered new diagnoses.

According to Samadder, who is a gastroenterologist specializing in hereditary cancers at the Mayo Clinic, these results emphasize the need for increased access to genomic screening for CDC Tier 1 (CDCT1) genetic syndromes. To meet CDCT1 status, genetic conditions must have significant potential for positive impact on public health based on available evidence-based guidelines and recommendations.

He noted that current clinical practice guidelines miss approximately 40% of individuals with high-risk hereditary cancer syndromes and that this number is in even greater in under-represented minorities—hovering at approximately 50%, a difference deemed statistically significantly (P = .05).

Specifically, among those who received a diagnosis of HBOC (n = 387) or LS (n = 163) through exome sequencing, 39.2% (n = 215) would not have met the NCCN guidelines for clinical testing. For patients with MSH6 and PMS2, the percentage of patients who did not meet NCCN clinical testing guidelines were 63.8% and 83.7%, respectively.

“Looking at the NCCN guidelines, which dictate who should undergo genetic evaluation and testing and [which] are frequently used by insurance companies for coverage of that testing, you can see here that out of the 550 carriers, nearly 40% would not have met NCCN criteria,” Samadder said. “NCCN criteria would have missed 50% of underrepresented minorities with HBOC and LS.” Samadder specified some reasons that these patients would have been missed by NCCN clinical guidelines: 58.6% had cancer types not related to genetic syndrome, 60.5% had an insufficient number of relatives with cancer, and 63.3% had no personal history of cancer.

Better testing for CDCT1 genetic conditions represent an opportunity to positively impact public health, according to Samadder. HBOC (BRCA1 and BRCA2) and LS (MLH1, MSH2, MSH6, PMS2, and EPCAM) are 2 key examples of CDCT1 genetic conditions which lead people to have a major predisposition for hereditary cancers. Traditionally, whether a patient was evaluated for LS and HBOC depended on their personal cancer history, including their family’s cancer history, their age at the time of cancer diagnosis, and their tumor features. However, as next-generation sequencing (NGS) whole-exome sequencing become more precise and more widely available, investigators are optimistic that it can be more broadly used. NGS whole-exome sequencing can detect greater than 85% of all disease-related variants, and its cost continues to rapidly decrease. This study was therefore designed to evaluate the ability of exome sequencing to effectively identify carries of HBOC and LS.

“[With] the ability to complete exome sequencing on saliva samples on thousands of patients, we can now approach comprehensive population-based whole-exome genomic sequencing to identify genetic carriers of disease,” Samadder said.

This study used the TAPESTRY clinical trial (NCT05212428), initiated at the 3 Mayo Clinic Cancer Centers in Arizona, Florida, and Minnesota. The study cohort included patients with a pathogenic mutation (and patients likely to have a pathogenic mutation) in BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, or EPCAM. Investigators reviewed the electronic health records of individuals with HBOC and LS to assess their demographics, personal and family history of cancer, and satisfaction of NCCN criteria.

This study included a total of 44,306 TAPESTRY participants, among whom, 550 were carriers of HBOC or LS. One hundred and sixty-three patients were diagnosed with LS and 387 were diagnosed with HBOC. Among those with an HBOC variant, 27.2% had BRCA1 and 42.8% had BRCA2. Among those with a LS variant, 4.5% had MLH1, 3.8% had MSH2, 12.3% had MSH6, 8.8% had PMS2, and 0.2% had EPCAM.

In the HBOC and LS populations, respectively, 47.3% and 44.2% had a personal history of cancer. A subtype breakdown showed that breast cancer (35.1% vs 10.2%), ovarian (7.1% vs 1.1%), colorectal (4.3% vs 26.1%), and uterine cancers (1.4% vs 13.6%) were the most common.

Moreover, 49.1% of patients with HBOC and 59.3% with LS did not have prior knowledge of their genetic condition. Specifically, 46.1% of patients with BRCA1, 51.0% of patients with BRCA2, 36.0% of patients with MLH1, 9.5% of patients with MSH2, 6.8% of patients with MSH6, and 81.6% of patients with PMS2, did not know they had this genetic condition prior to exome sequencing.

In addition, findings revealed that even when patients meet practice guidelines, they are still being undertested. In this study, 34% of patients who met NCCN guidelines for CDCT1 testing had not been screened for those genetic conditions.

“Our results emphasize the need for increased access to genomic screening for CDCT1 genetic conditions and [the] potential use of exome sequencing in large populations,” he concluded.

Editor’s Note: Dr Samadder reported financial disclosures with Jansen Research and Development, Cancer Prevention Pharmaceuticals, and Recursion Pharmaceuticals.


Gay E, Jewel Samadder N, Bublitz M. Genetic screening in a tertiary medical center identifies carriers of cancer predisposition diseases that would be missed by clinical guidelines. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orando, FL.

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