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ACMG Workgroup Addresses Cancer Risk Variability With CHEK2 Alterations in Practice Resource

NEW YORK – A clinical practice resource from the American College of Medical Genetics and Genomics (ACMG) suggests that medical geneticists and other clinicians should consider the type of heterozygous CHEK2 variant a patient has along with family history and other modifiers when gauging cancer risk and determining prevention strategies.

While studies have been published on the association between CHEK2 variants and cancer risk, it has been challenging to develop guidelines on how to manage patients with these variants because early studies have focused mostly on common variants, and studies, depending on their design and the population evaluated, have yielded different penetrance estimates for the same variants. In an effort to reduce the variability in managing patients with heterozygous CHEK2 variants, an ACMG workgroup published a resource in Genetics in Medicine on Tuesday having evaluated the latest published research on the prevalence and role of different variants in breast and other cancers. 

Overall, researchers found strong evidence that CHEK2 truncating variants are associated with a moderate risk of breast cancer and evidence that such variants confer a moderate risk of prostate cancer and a low-moderate risk of colorectal cancer. However, they also cautioned in the paper that unlike other breast cancer predisposition genes, such as BRCA1 and BRCA2, where heterozygous carriers of pathogenic variants are considered at high risk, there is a "substantial variance in distribution of risk for CHEK2 heterozygotes."

For example, the most well-known and -studied CHEK2 variant, called c.1100del, is a truncating variant that is associated with a nearly twofold higher cancer risk. The ACMG workgroup confirmed that these CHEK2 truncating variants had a "definite association" with breast cancer predisposition, and one missense CHEK2 variant, p.(Arg117Gly), was found to have similar cancer risk association as the truncating variants.

However, other missense variants had a weaker association with cancer risk. The available data on heterozygote missense CHEK2 p.(Ile157Thr) and p.(Ser428Phe) variants, for example, did not reach the workgroup's threshold for clinical actionability and required further research.

This variability in risk across different types of CHEK2 alterations requires a more personalized approach when managing and providing genetic counseling to patients who carry these variants, Douglas Stewart, senior author of the paper and a senior investigator in the Clinical Genetics Branch at the National Cancer Institute, said in an emailed comment.

The workgroup recommended that clinicians consider CHEK2 variants alongside family history, hormonal and reproductive risk factors, and mammographic density when assessing breast cancer risk. For instance, patients harboring some missense CHEK2 variants may not need as intensive cancer surveillance as those with truncating CHEK2 variants.

"CHEK2-associated cancer risk is complex and is affected by multiple factors, including the specific variant, family history, and non-CHEK2 genetic background," Stewart continued. "An important theme in the guidance is that personalized — rather than generalized — risk must be assessed by a specialist in cancer genetics. These personalized risk estimates can then guide shared decision-making about surveillance and risk-reduction."

In other tumor types, the researchers concluded that more evidence was needed to identify a clear association with CHEK2 variants and cancer risk. While for colorectal and prostate cancers the group found evidence that CHEK2 variants conferred moderate and low-moderate cancer risk, respectively, they found insufficient evidence on the association between variants in this gene and other tumors including male breast, stomach, kidney, thyroid, pancreatic, and pediatric cancers.

"The degree of CHEK2-associated risk is uncertain or unknown for many cancers," Stewart said. "For the cancers in which there is a clear association, like breast cancer, the penetrance is modest, making management a challenge."

The workgroup also explored whether CHEK2 variants influenced the pathology, outcomes, or treatment strategies for breast cancer. While studies have suggested CHEK2 was associated with estrogen receptor-positive breast and lobular breast cancer, the researchers found little association between variants in this gene and survival outcomes.

After evaluating the available evidence, they also found a dearth of data supporting the use of CHEK2 status to guide targeted treatment decisions. They noted that there have been few clinical trials exploring different treatments in CHEK2-associated breast cancer. The ACMG workgroup further did not recommend clinicians routinely offer a risk-reducing mastectomy for patients with CHEK2 pathogenic variants unless other clinical factors suggested a high risk of cancer occurrence.

"Compared with highly penetrant cancer-risk genes like BRCA1 or BRCA2, there is a paucity of data on risk of cancer and clinical outcomes from most pathogenic variants in CHEK2," Stewart said.