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Actionable Mutation Analysis Reveals Germline Risk in Older CRC Patients

NEW YORK – Results from a community-based analysis of actionable germline mutations in individuals with or without colorectal cancer (CRC) or colon polyps suggest a potential benefit to doing hereditary cancer risk testing in CRC patients diagnosed at advanced ages.

In an effort to establish baseline information on actionable mutations and incidental findings, a team led by investigators at the University of Washington analyzed the proportion of healthy individuals, CRC patients, or individuals with polyps from a Washington state community setting who carried pathogenic or likely pathogenic variants in CRC-genes or in genes deemed actionable under American College of Medical Genetics and Genomics (ACMG) guidelines.

"As genomic screening for high penetrance gene-disease pairs is proposed and implemented, understanding the rate of positive tests is important for informed consent and planning adequate resources for follow up," senior author Gail Jarvik, a medicine and genome sciences researcher at the University of Washington, and her colleagues wrote, noting that the results "suggest that current testing strategies could be improved in order to better detect Mendelian [colorectal cancer]-associated conditions."

As they reported online today in the American Journal of Human Genetics, Jarvik and her colleagues looked at eMERGEseq panel sequencing profiles spanning 109 genes for 529 participants with CRC, 636 individuals with polyps, and 590 unaffected control individuals — participants tested between 2008 and 2017 who were drawn from the University of Washington and Kaiser Permanente Washington Health Research Institute biorepository, known as the Northwest Institute for Genomic Medicine.

They found that 3.8 percent of the CRC patients carried pathogenic or likely pathogenic mutations in CRC- or polyp-related genes, even though many of the patients were diagnosed with cancer at relatively advanced ages (72 years old, on average). In contrast, risky variants in those genes turned up in 0.8 percent of polyp patients and in 0.2 percent of the unaffected controls.

"The majority of these positives (85 percent) were in Lynch syndrome genes, putting the individuals at risk for non-CRC cancers which could be screened for, particularly endometrial cancer in women," the authors noted. "Further, these results have significance for those family members who may share the pathogenic variant."

The team's analysis of non-CRC-related genes unearthed actionable mutations in comparable proportions of CRC patient, polyp, and control groups. In the CRC patient group, for example, some 2.8 percent of individuals had pathogenic or likely pathogenic mutations in genes related to non-CRC conditions compared to 2.5 percent in individuals with polyps and 2 percent of unaffected controls.

Even so, the authors cautioned that actionable mutations with proposed ties to cardiovascular disease turned up more often than anticipated, in 0.85 percent of the participants — outpacing the rates of cardiovascular disease that are typically found in the general population. That suggests at least some of the incidental findings (IFs) involving cardiovascular genes may be aberrantly classified as pathogenic or likely pathogenic, they explained. 

"[C]ardiac IFs were more frequent than expected based on population prevalence, suggesting that pathogenic variants in these genes may be of lower penetrance or some of the reported variants, particularly the [likely pathogenic], may not be pathogenic," the authors concluded, adding that "[c]linical return of incidental [likely pathogenic] variants for these less-studied genes may be imprudent, particularly if the biological mechanism underlying a given disease association remains poorly understood."

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