Exome sequencing identifies cancer predisposition-gene carriers screening guidelines miss

April 19, 2023 12:55 pm

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AACR 2023 meeting

by Jennifer Southall

Whole-exome sequencing identified carriers of predisposition genes for hereditary breast and ovarian cancer or Lynch syndrome who, under current guidelines, would not have qualified for genetic testing, according to study results.

The findings, presented at American Association for Cancer Research Annual Meeting, highlighted the need for wide genomic screening for inherited autosomal dominant cancer predisposition conditions, dubbed CDC Tier 1 genetic conditions, for which early identification and intervention could have a positive impact on public health, researchers noted.

Background and methods
There has been a revolution in genomic sequencing capabilities over the past decade as costs of genetic testing have decreased and knowledge of gene-phenotype correlations and effective cancer screening has expanded, N. Jewel Samadder, MD, professor of medicine at Mayo Clinic College of Medicine and co-leader of the precision oncology program at Mayo Clinic Comprehensive Cancer Center, told Healio.

“With these advances, consideration for genomic screening in the broad general population has garnered increasing attention,” he said. “The Tapestry trial provides an important landscape on which to learn about the clinical value, acceptability, implementation, feasibility and economic value of genomic screening for early detection in unselected populations.”

The Genomics and Population Health Action Collaborative endorsed the 11 genes associated with the three CDC Tier 1 conditions — hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial hypercholesterolemia — as being a reasonable starting point for primary genomic screening in the general population, Samadder added.

Key takeaways:

    • More than half of individuals appeared unaware they carried predisposition genes.
    • Nearly 40% of carriers would not have met NCCN criteria for genetic screening.


“The aim of this study was to evaluate whether screening in a multisite tertiary medical center using exome sequencing could efficiently identify carriers of two conditions and determine the frequency of incremental carriers identified outside of traditional clinical practice guidelines,” he said.

The study focused on identifying carriers of hereditary breast and ovarian cancers and Lynch syndrome. Researchers additionally sought to determine the frequency of incremental carriers identified outside of traditional clinical practice guidelines.

N. Jewel Samadder, MDThe Tapestry trial included 44,306 patients (mean age, 55.2 years; 62.7% women; 90.4% white) who received treatment across Mayo Clinic sites in Minnesota, Arizona and Florida. Researchers gathered and evaluated saliva samples for pathogenic mutations in BRCA1 and BRCA2 (denoting hereditary breast and ovarian cancer), as well as MLH1, MSH2, MSH6, PMS2 and EPCAM (denoting Lynch syndrome).

Researchers identified 550 carriers of pathogenic mutations, including 387 individuals with hereditary breast and ovarian cancer and 163 with Lynch syndrome. More than half (52.1%) had no prior knowledge that they carried predisposition genes.

Results showed 39.2% of carriers did not meet NCCN criteria for genetic testing, including 56.2% of those with Lynch syndrome and 32% of those with hereditary breast and ovarian cancer.

Sixty-percent of the 286 individuals newly diagnosed with hereditary breast and ovarian cancer and Lynch syndrome during the study appeared ineligible for genetic testing per current guidelines. They included 78% of those with Lynch syndrome and 51% of those with hereditary breast and ovarian cancer.

Reasons for not meeting NCCN criteria included having no personal history of cancer (63.3%), an insufficient number of relatives who had cancer (60.5%) and a cancer type or types not related to a genetic syndrome (58.6%).

Among those who met NCCN guidelines for testing, 34.2% reported not knowing their diagnosis prior to the study.

Researchers additionally found that individuals with hereditary breast and ovarian cancer or Lynch syndrome from racial and ethnic minority groups appeared significantly more likely than white patients to not meet NCCN screening criteria (49% vs. 32%).

Limitations of the study included the exclusivity of the patient population that may not reflect the demographics of the general population, according to the researchers.

The findings suggest that genetic screening for CDC Tier 1 conditions has the potential to identify 50% of at-risk carriers who are not detected in current medical practice and bypass the convoluted and insensitive phenotype and family-history based guidelines currently utilized, Samadder told Healio.

“Cost-effectiveness studies support such a population-genomic approach in those younger than 45 years when testing costs fall below $500,” he said. “This approach would also provide a more equitable distribution of genomic diagnosis to underrepresented minority populations. However, population health genetic screening approaches need additional implementation studies prior to standard-of-care clinical practice adoption to evaluate cost, overinterpretation of disease risk, impact on standard-of-care cancer screening, and ethical and social factors.”

Researchers aim to enroll 100,000 patients in the current study before completion of final analyses. They also intend to conduct a substudy that follows patients for 10 years to identify how the information gained from whole-exome sequencing impacts their health, according to a press release.

Exome sequencing identifies individuals with cancer predisposition syndromes missed by current screening guidelines (AACR press release). Available at: www.aacr.org/about-the-aacr/newsroom/news-releases/exome-sequencing-identifies-individuals-with-cancer-predisposition-syndromes-missed-by-current-screening-guidelines/. Published April 18, 2023. Accessed April 18, 2023.
Gay E, et al. Abstract 5768. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando.

This article was published by Healio.

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