Risk of Colorectal Cancer Varies Widely in Lynch Syndrome Carriers

By Marilynn Larkin

June 24, 2021

NEW YORK (Reuters Health) - Familial and environmental factors influence colorectal cancer risk for Lynch syndrome carriers globally, signaling the need for personalized risk assessments and prevention strategies for these patients, researchers say.

"Our findings will not change practice yet," Dr. Mark Jenkins of the University of Melbourne told Reuters Health by email. "Even though we now know how many mutation carriers are at low risk, and how many at high risk, we don't yet have the technology to determine which risk group an individual person is in - but we are working towards this."

"We are developing a risk tool that takes into account all the risk factors for colorectal cancer so we can determine personalized cancer risk for people with Lynch syndrome," he said. "These factors include family history, aspirin, BMI and smoking. We are also looking at the variation in risk of cancer of the uterus (endometrial cancer) which is also elevated for women with Lynch syndrome."

As reported in The Lancet Oncology, Dr. Jenkins and colleagues sourced data from the International Mismatch Repair Consortium. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included in the analysis and families of probands with known de-novo pathogenic variants were excluded.

Sufficient data were available for 5,255 families (1,829 MLH1; 2,179 MSH2; 798 MSH6; and 449 PMS2), consisting of 79,809 relatives recruited in 15 countries in North America, Europe, and Australasia.

Strong evidence suggested the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers across the continents. These factors resulted in a wide within-gene variation in colorectal cancer risk for men and women who carried pathogenic variants in the same gene or the MSH2 c.942+3A>T variant.

The majority of carriers were either at the lower end (average population risk) or the upper end (almost certain to develop colorectal cancer during their lifetime) of the risk distribution.

The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7%-56% of carriers having a colorectal cancer penetrance of less than 20%; 9%-44% having a penetrance of more than 80%; and only 10%-19% having a penetrance of 40%-60%.

While clinicians can't do anything clinically with the findings as yet, Dr. Jenkins said, they should "be aware that for people with Lynch syndrome, the risk of colorectal cancer probably depends on their family history of colorectal cancer."

Gastroenterologist Dr. Aimee Lucas, associate professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, commented on the study by phone. "What's really interesting is the wide variation in cancer risk that they see within each gene and that the average risk that we see for each gene basically doesn't apply to the vast majority of patients in their cohort," she told Reuters Health. "This adds more strength to the argument that outside factors impact cancer risk."

"It's a challenge to give patients a very wide risk range, and the temptation is to narrow it down for them," she said. "But this study tells us that there might be undetected factors such as polygenic risk factors or environmental factors that we don't know about and that really impact colon cancer risk in some of these patients."

Like Dr. Jenkins, she said, "It's not just about which gene patients have. It's still very important to take a family history of a variety of cancers, because family history can be a proxy measure for other risk factors, such as polygenic risk or shared environmental risk. Family history should also be taken into account when we're considering screening and surveillance practices for Lynch Syndrome patients."

SOURCE: https://bit.ly/3d8nCiq and https://bit.ly/3gU6spM The Lancet Oncology, online June 7, 2021.