How Whole Exome Sequencing Improves Identification of People With Cancer Predisposition Syndromes

Among individuals who consented to whole-exome sequencing (WES) and were identified as carriers of predisposition genes for hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC), 39.2% would not have qualified for genetic screening under current guidelines. This conclusion is based on results from the Tapestry clinical trial presented at the annual meeting of the American Association for Cancer Research (AACR), held April 14-19, 2023 at the Orange County Convention Center in Orlando, Florida.

The study was funded by the Mayo Clinic Center for Individualized Medicine.

The early identification and prevention of these two inherited autosomal dominant cancer predisposition conditions, has, no doubt, a positive impact on public health.

Whole-exome sequencing, an application of Next-generation sequencing (NGS), is potentially the most powerful type of genetic sequencing available.  The technology has revolutionized the understanding in medical genetics, potentially leading to personalized medicine.

Because whole-exome sequencing covers more than 95% of the exons which include nearly 85% of the disease-causing mutations and disease predisposition syndromes, it can be used to better understand the causes of disease. For example, whole-exome sequencing can highlight novel insights into cancer mechanisms. [2] Furthermore, the identification of the DNA sequence of cancer cells, in comparison to normal or health cells, can improve the understanding of cancer. In addition, sequence variations may help the identify people with a predisposition for the development of different forms of hereditary cancer or hematological diseases. [2]

Approximately 5 – 10% of all breast cancers patients are genetically predisposed to cancers. However, research shows that only 25% of cases of HBOC can be ascribed to most common breast cancer susceptibility genes BRCA1 and BRCA2 mutations.  Recent whole exome sequencing technology has resulted in the discovery of several non-BRCA genes responsible for breast. And this poses a challenge in the estimation of risk management and treatment decision-making.[3]

A markedly increased risk
“Patients with hereditary breast and ovarian cancer have up to an 80% 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,” noted Niloy 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.

“And patients with Lynch syndrome have up to an 80% lifetime risk of colorectal and 60% lifetime risk of endometrial cancer, with additional increased risks of upper gastrointestinal, urinary tract, skin, and other cancers,” Samadder added.

Both of these conditions are classified by the Centers for Disease Control and Prevention (CDC) as Tier 1 genetic conditions (CDCT1).

In this disease category, which also includes primarily familial hypercholesterolemia, genetic variants related to these conditions are highly penetrant, significantly increase the odds of disease development over non-carriers. Hence, early detection of these conditions and proactive intervention could significantly improve public health.

Guidelines
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.

“If individuals know about their genetic risk for certain cancers, they can undergo enhanced screening and consider prophylactic surgeries,” Samadder explained .

A prophylactic approach
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, Samadder explained.

“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,” Samadder noted.

“However, these conditions are poorly identified in current practice, and many patients are not aware of their cancer risk,” she added.

Cheaper and more accessible
According to the National Institute of Health’s National Human Genome Research Institute, the costs of whole exome sequence has fallen below US $ 1,000, with commercial proces generally below these costs. And because 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* (NCT05212428) 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 Rochester MN, Phoenix AZ, and Jacksonville 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 BRCA1 and BRCA2, denoting HBOC, and 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 (27.2% BRCA1, 42.8% BRCA2) and 163 with Lynch syndrome (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2 and 0.2% EPCAM).

Of these individuals, 62.7% were female, mean age 55.2 years, non-white race 9.6% and 3.8% Hispanic/Latino ethnicity. A personal history of cancer was present in 46.4% of test positive patients, including 22.5% of patients diagnosed with hereditary breast and ovarian cancer (HBOC) and 20.9% were diagnosed with Lynch syndrome patients with colorectal
or uterine cancer.

In addition, 52.1% did not know prior to this study that they had a cancer predisposition condition and 39.2% did not satisfy the existing NCCN criteria for genetic testing, this was higher for Lynch syndrome patients (56.2%) compared to HBOC patients (32%).

Among the patients who were newly diagnosed with Lynch syndrome or HBOC during this study (n=286), 60% were ineligible for genetic testing per the current guidelines (78% for Lynch syndrome and 51% for HBOC). .

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% versus 32%, respectively).

Samadder suggested that this may indicate a systemic bias in the current guidelines that could potentially be overcome by universal genetic testing.

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.

Taking control
“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,” Samadder said.

“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.”

Study limitations
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 an enrollment of 10% underrepresented minorities, a number Samadder and colleagues intend to increase as the study continues recruitment.

Clinical trial
DNA Sequencing in Clinical Practice, Mayo Clinic Health Tapestry Study – NCT05212428

Clinical trial summary
This trial is designed to collect information on how sequencing a patient’s deoxyribonucleic acid (DNA) could impact their health care. In addition, the study develops and improves ways to include genomic information from DNA sequencing into the electronic health record to create a more complete Health Tapestry for each participant. Sequencing of a patient’s DNA leads to the detection of genetic variants some of which determine risk for disease development. Discovery of those genetic variants in a patient could result in prevention, earlier diagnosis or better therapy of disease.

Highlights of Prescribing Information

Reference
[1] Gay E, Samadder NJ, Bublitz ML, Peterson MM, Wilson TA, Bandel LA, Armasu SM, Vierkant RA , Ferber MJ, Klee EW, Larson NB, Kruisselbrink TA, Curry TB, et al. 
Genetic screening in a tertiary medical center identifies carriers of cancer predisposition
diseases that would be missed by clinical guidelines. In: Proceedings of the 114th Annual Meeting of the American Association for Cancer Research; 2023 April 14-19; Orlando, FL. Philadelphia (PA): AACR; 2023. Abstract nr 5768
[2] Yan XJ, Xu J, Gu ZH, Pan CM, Lu G, Shen Y, Shi JY, Zhu YM, Tang L, Zhang XW, Liang WX, Mi JQ, Song HD, Li KQ, Chen Z, Chen SJ. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet. 2011 Mar 13;43(4):309-15. doi: 10.1038/ng.788. PMID: 21399634.
[3] Nielsen FC, van Overeem Hansen T, Sørensen CS. Hereditary breast and ovarian cancer: new genes in confined pathways. Nat Rev Cancer. 2016 Sep;16(9):599-612. doi: 10.1038/nrc.2016.72. Epub 2016 Aug 12. PMID: 27515922.

Featured image by National Cancer Institute on Unsplash.