Retrospective Study Explores Variation in Colorectal Cancer Risk in Families With Lynch Syndrome

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In a retrospective cohort study reported by Win et al in The Lancet Oncology, researchers in the International Mismatch Repair Consortium found marked variation in the risk of colorectal cancer in families with Lynch syndrome carrying the same pathogenic variant in DNA mismatch repair genes. The findings indicate the presence of additional as-yet unidentified factors may be responsible for wide variation in risk across Lynch syndrome carriers.

Study Details

The study used data from the International Mismatch Repair Consortium, which includes sites in 32 countries involved in Lynch syndrome research. Families with at least three members and at least one carrier of a pathogenic variant in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2 were included in the study. Analysis of colorectal cancer penetrance according to mismatch repair genes was accompanied by modeling of an unmeasured polygenic component that included the combined effects of common colorectal cancer risk factors correlated within families.

Our study findings highlight the important role of risk modifiers, which could lead to personalized risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome.
— Win et al

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Key Findings

Among 5,585 families with Lynch syndrome from 22 countries eligible for the analysis, there was insufficient data to estimate colorectal cancer penetrance for Asia and South America and for individuals with EPCAM pathogenic variants. The analysis thus included data collected between July 2014 and December 2018 from 5,255 families (1,829 MLH1, 2,179 MSH2, 798 MSH6, and 449 PMS2), including 79,809 relatives from 15 countries in North America, Europe, and Australasia.

On average, the penetrance of colorectal cancer was highest for MLH1 and MSH2 variant carriers and lowest for PMS2 variant carriers.

Strong evidence was observed for the existence of unknown familial risk factors modifying colorectal cancer risk for patients with Lynch syndrome in each of the three continents (P < .0001 for each). The hazard ratios per one polygenic standard deviation (SD; a measure of variation in risk between individual carriers with the same sex, age, and mutated gene) were 5.4 for carriers from Europe, 5.1 for carriers from North America, and 3.5 for carriers from Australasia.

These additional factors accounted for wide within-gene variation in colorectal cancer risk for men and women from each continent who carried pathogenic variants in the same gene or the MSH2 c.942+3A>T variant. The variation was particularly marked among MLH1 and MSH2 variant carriers: across gene, sex, and continent, 7% to 56% of carriers had colorectal cancer penetrance of < 20%, 10% to 19% had penetrance of 40% to 60%, and 9% to 44% had penetrance of > 80%. In analysis restricted to 250 families carrying the specific MSH2 pathogenic variant c.942+3A>T, 9% to 15% had penetrance of < 20% and 33% to 45% had penetrance of > 80%. The majority of MSH6 and PMS2 carriers were estimated to have penetrance of < 20%, with a very small proportion having penetrance of > 80%.

Examples of variability included European MLH1 carriers, with estimates of colorectal cancer penetrance of < 20%, 40% to 60%, and > 80% for 44%, 12%, and 15% of women and 23%, 14%, and 33% of men. Among North American MLH1 carriers, colorectal cancer penetrance was < 20%, 40% to 60%, and > 80% in 31%, 14%, and 23% of women and 22%, 14%, and 33% of men. Among Australasian carriers, penetrance at these levels was observed for 20%, 19%, and 22% of women and 14%, 18%, and 30% of men.

The investigators stated, “First, for families, segregating any pathogenic variant in a DNA mismatch repair gene, the pathogenic variant did not account for all the observed family history of the disease. This observation is consistent with the existence of risk factors, which modify the risk of colorectal cancer in Lynch syndrome carriers, that are yet to be identified but are shared by relatives, including polygenic factors. Second, these risk modifiers…are strong and common enough to cause a wide variation in the risk of colorectal cancer across Lynch syndrome carriers—the majority of carriers were either at the lower end (at the average population risk) or the upper end (almost certain to develop colorectal cancer during their lifetime) of the risk distribution. Finally, this observed variation in colorectal cancer risk for Lynch syndrome carriers exists internationally, with similar findings across the three continents examined.”

They concluded, “Our study findings highlight the important role of risk modifiers, which could lead to personalized risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome.”

Mark A. Jenkins, PhD, of the Melbourne School of Population and Global Health, University of Melbourne, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the Australian National Health and Medical Research Council. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.