Exome Sequencing Identifies Patients with HBOC Missed by Current Screening Guidelines

ORLANDO, FL — Among individuals who consented to whole-exome sequencing and were identified as carriers of predisposition genes for hereditary breast and ovarian cancer (HBOC) or Lynch syndrome, 39.2 percent would not have qualified for genetic screening under current guidelines, according to results from the Tapestry clinical trial presented at the recently held AACR Annual Meeting 2023.

Patients with HBOC genes have up to an 80 percent lifetime risk of developing breast cancer and a markedly increased risk, relative to the general population, of developing ovarian cancer, pancreatic cancer, prostate cancer, and melanoma, said N. Jewel Samadder, MD, a 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, who co-led the study.

Patients with Lynch syndrome have up to an 80 percent and 60 percent lifetime risk of colorectal and endometrial cancer, respectively, with additional increased risks of upper gastrointestinal, urinary tract, skin, and other cancers.

Both of these conditions are classified by the CDC as Tier 1 genetic conditions (CDCT1), meaning that early detection of these conditions and proactive intervention could significantly improve public health. The National Cancer Control Network (NCCN) has established a set of guidelines based on an individual’s family and personal history of cancer to identify individuals who should undergo genetic testing for these conditions.

Pitfalls of current genetic screening practices

If individuals know about their genetic risk for certain cancers, they can undergo enhanced screening and consider prophylactic surgeries, explained Samadder. For patients with Lynch syndrome, this can include regular colonoscopies, blood and urine screening, and prophylactic hysterectomy. For patients with HBOC, this can include advanced breast imaging and prophylactic mastectomy and/or oophorectomy.

Despite the potential benefits, these criteria are not always adequately applied, and even when used appropriately, they do not catch everyone who should be screened, said Samadder.

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

The Tapestry study: enrolment, analysis, discrepancies

As whole-exome sequencing becomes cheaper and more accessible, Samadder and colleagues hypothesized that the benefits of screening a broader population may outweigh the costs. They initiated the Tapestry study to investigate whether whole-exome sequencing could provide individuals with more robust information about their genetic predisposition for certain diseases.

At the time of data cut-off, 44,306 patients from Mayo Clinic sites in MN, AZ, and FL had enrolled in the study. Each individual provided a saliva sample that was subjected to whole-exome sequencing. For this portion of the study, researchers evaluated samples for pathogenic mutations in genes BRCA1 and BRCA2 denoting HBOC, and genes MLH1, MSH2, MSH6, PMS2, and EPCAM denoting Lynch syndrome.

Samadder and colleagues identified 550 carriers of pathogenic mutations in these genes, comprising 387 individuals with HBOC and 163 with Lynch syndrome. Of these individuals, 52.1 percent did not know prior to this study that they had a cancer predisposition condition and 39.2 percent did not satisfy the existing NCCN criteria for genetic testing. 

Among the patients who were newly diagnosed with Lynch syndrome or HBOC during this study, 60 percent were ineligible for genetic testing per the current guidelines.

Patients with HBOC or Lynch syndrome from racial and ethnic minority groups were significantly more likely than White patients to not meet NCCN screening criteria (49 percent versus 32 percent, respectively). Samadder suggested that this may indicate a systemic bias in the current guidelines that could potentially be overcome by universal genetic testing.

Decentralizing whole-exome sequencing for cancer screening

The study aims to enroll a total of 100,000 patients before completing its final analyses, which will include a sub-study that follows patients for 10 years to observe how the information gained from whole-exome sequencing impacts 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,” said Samadder. “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.”

Limitations of this study include the exclusivity of the patient population to individuals enrolled in the Mayo Clinic system, a tertiary and quaternary care system that may not reflect the demographics of the general population. This includes the enrollment of 10 percent underrepresented minorities, a number Samadder and colleagues intend to increase as the study continues recruitment.

- This press release was originally published on the American Association for Cancer Research website