Whole-Exome Sequencing May Help Identify Individuals With Cancer Predisposition Syndromes Missed by Current Screening Guidelines

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Researchers revealed that 39.2% of patients who consented to whole-exome sequencing and were identified as carriers of predisposition genes for hereditary breast and ovarian cancer or Lynch syndrome did not qualify for genetic screening under current guidelines, according to new findings presented by Samadder et al at the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 1921).


Patients with hereditary breast and ovarian cancer may have up to an 80% lifetime risk of developing breast cancer and a markedly increased risk of developing ovarian cancer, pancreatic cancer, prostate cancer, and melanoma compared with the general population. Further, patients with Lynch syndrome may have up to an 80% and 60% lifetime risk of developing colorectal cancer and endometrial cancer, respectively, with an additional increased risk of developing upper gastrointestinal cancer, bladder cancer, skin cancer, and other solid tumors.

Both of these conditions have been classified as Tier 1 genetic conditions by the U.S. Centers for Disease Control and Prevention, meaning that early detection of these conditions and proactive intervention could significantly improve public health. The National Comprehensive Cancer Network (NCCN) has established a set of guidelines—based on an individual’s family and personal history of cancer—to identify those who should undergo genetic testing for these conditions.

Individuals who are aware of their genetic risk for certain cancers can undergo enhanced screenings and prophylactic surgeries. For patients with hereditary breast and ovarian cancer, this can include advanced breast screenings and prophylactic mastectomies and/or oophorectomies. For patients with Lynch syndrome, this can include regular colonoscopies, blood and urine screenings, and prophylactic hysterectomies. Despite the potential benefits, these criteria are not always adequately applied, and even when used appropriately, they may not identify all individuals who may need to undergo screenings.

“These criteria were created at a time when genetic testing was cost-prohibitive, and thus, aimed to identify those at … greatest [risk] of being a mutation carrier in the absence of population-wide whole-exome sequencing,” explained co–lead study author Niloy Jewel Samadder, MD, MSc, Professor of Medicine at the Mayo Clinic and Co-Leader of the Precision Oncology program at the Mayo Clinic Comprehensive Cancer Center. “However, these conditions are poorly identified in current practice, and many patients are not aware of their cancer risk,” he added. As whole-exome sequencing becomes cheaper and more accessible, Dr. Samadder and his colleagues hypothesized that the benefits of screening a broader population may outweigh the costs.


  • Among the 44,306 study participants, 1.2% were found to have a cancer predisposition syndrome after undergoing whole-exome sequencing.
  • Among the participants newly diagnosed with a predisposition, 60% were ineligible for genetic testing according to NCCN guidelines.
  • Racial or ethnic minority participants were less likely (49%) to be eligible than White participants (32%).

Study Methods and Results

In the new Tapestry clinical trial ( identifier NCT05212428), the researchers asked 44,306 participants to provide saliva samples for whole-exome sequencing in order to investigate whether the method could provide individuals with more robust information about their genetic predisposition for certain cancer types. The researchers then evaluated the saliva samples for pathogenic mutations in the BRCA1 and BRCA2 genes, denoting hereditary breast and ovarian cancer, as well as the MLH1, MSH2, MSH6, PMS2, and EPCAM genes, denoting Lynch syndrome.

They identified 550 carriers of pathogenic mutations in these genes, comprising 387 individuals with hereditary breast and ovarian cancer and 163 individuals with Lynch syndrome. Among these individuals, 52.1% of them were unaware that they had a cancer predisposition syndrome prior to the study and 39.2% did not satisfy the existing NCCN criteria for genetic testing. Among the patients who were newly diagnosed with hereditary breast and ovarian cancer or Lynch syndrome during this study, 60% of them were ineligible for genetic testing per the current guidelines.

Further, the researchers discovered that study participants with hereditary breast and ovarian cancer or Lynch syndrome from racial and ethnic minority groups were significantly more likely than White study participants to not meet NCCN screening criteria (49% vs 32%, respectively). The researchers suggested that this may indicate a systemic bias in the current guidelines that could potentially be overcome by universal genetic testing.


The researchers noted that they aim to enroll a total of 100,000 patients before completing their final analyses, which will include a substudy following patients for 10 years to observe how the information gained from whole-exome sequencing may impact their health.

“The knowledge that comes from genetics can empower patients to take control of their disease risk and increase their likelihood of avoiding a deadly cancer diagnosis or catching it at an early stage when it is highly curable,” Dr. Samadder underscored. “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,” he concluded.

Disclosure: The research in this study was funded by the Mayo Clinic Center for Individualized Medicine. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.