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Multi-Gene Panel Testing Finds Pathogenic Variant Carriers Missed Under Current Testing Guidelines

NEW YORK (GenomeWeb) – Multi-gene panel testing can identify patients who are carriers of pathogenic variants who might otherwise be missed under current genetic testing guidelines, according to a new study from Color researchers.

Current guidelines, such as the ones from the National Comprehensive Cancer Network (NCCN), recommend genetic testing for people who have a personal or family history of cancer that indicates they might be at an increased risk of harboring a pathogenic familial variant. But this approach could miss people who lack any personal or family history.

Alicia Zhou, vice president of research and scientific affairs at Color, and her colleagues sifted through multi-gene panel testing data they gathered on more than 23,000 individuals. As they reported in the Journal of Molecular Diagnostics today, they found pathogenic variants — and sometimes more than one pathogenic variant — in nearly 2,700 people. A portion of these individuals, though, did not meet guidelines for hereditary cancer testing.

"[T]he results indicate that more individuals are at genetic risk for hereditary cancer than are identified by current testing guidelines and/or use of single-gene or single-site testing," the researchers wrote in their paper.

For their retrospective study, the researchers analyzed testing results for 23,179 individuals who took the Color Hereditary Cancer test between May 2016 and September 2017. This test analyzes 30 genes in which pathogenic variants have been associated with an increased risk of hereditary cancers, including breast, ovarian, colorectal, and other cancers. The genes analyzed encompass BRCA1, BRCA2, CDKN2A, PTEN, TP53, and more.

Within this cohort, the researchers identified 2,811 pathogenic variants in 2,698 individuals, an overall pathogenic variant frequency of 11.6 percent. Pathogenic variants in BRCA1 and BRCA2 accounted for nearly a third of all positive results, while pathogenic variants linked to Lynch syndrome accounted for another 7.0 percent of results.

The researchers noted that pathogenic variants in BRCA1 or BRCA2 could be found across ethnic groups.

While most individuals with a positive result harbored only a single pathogenic variant, a small number had two or more pathogenic variants, such as in BRCA1 or BRCA2 and in another cancer-linked gene.

NCCN guidelines recommend genetic counseling and testing for individuals who are thought to be at a high risk of a genetic cancer syndrome based on personal and family history. 

Of the 18,176 individuals in their cohort with sufficient health histories, 61.3 percent met criteria for genetic testing for breast, ovarian, colorectal, or gastric cancer and 38.7 percent did not.

Among those patients who did not meet testing criteria — but who underwent testing anyway — the researchers reported an 8.2 percent pathogenic frequency and, of those, 21.7 percent had pathogenic variants in genes with well-established testing criteria.

That means that of the 749 individuals they identified with a pathogenic variant in BRCA1, BRCA2, TP53, or PTEN, 18.4 percent would not have met testing guidelines for breast and ovarian cancer. Similarly, slightly more than a third of the individuals they identified with Lynch syndrome-linked variants would not have met testing criteria.

This underscores that current testing approaches may miss some individuals at increased genetic risk of cancer, Color's Zhou and her colleagues said.

They noted that one concern with broader genetic testing is that it could have negative psychological effects. But they argued in their paper that other studies have recently reported that screening does not appear to affect short-tern psychological or quality-of-life outcomes.

This suggested to them that their findings support a push for population-based genetic testing for hereditary cancers.