Individuals with PMS2 pathogenic variants are at average risk of cancer before age 60
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Importance
Screening Lynch syndrome in the general population, including healthy individuals, aims to detect and prevent cancers early. Current clinical recommendations for those with pathogenic variants are based on studies of patients with cancer or strong family history. It is essential to ensure guidelines are based on accurate assumptions regarding the impact of pathogenic variants in Lynch syndrome genes.
Objective
To determine the risk of cancer associated with pathogenic variants in MLH1, MSH2, MSH6 , or PMS2 in the general population.
Design, Setting, and Participants
This retrospective case-control study utilizes Helix Research Network ™ data from 144,852 participants across seven US health systems sequenced between 2018 and 2024.
Main outcomes and measures
An automated pipeline based on the ACMG-AMP guidelines was developed for variant interpretations. Clinical diagnoses were identified from electronic health records for 11 cancer types associated with Lynch syndrome including colorectal and endometrial cancers.
Results
Individuals with pathogenic variants in MLH1, MSH2 , and MSH6 were at significantly increased risk for Lynch syndrome-associated cancers with Hazard Ratios (HR) of 16.5 (95% Cl: 8.9-30.8) for MLH1 , 17.3 (7.8-38.6) for MSH2 and 4.7 (3.2-6.9) for MSH6 . No significant risk was associated with PMS2 pathogenic variants when considering all 11 cancers combined. PMS2 pathogenic variants were only associated with colorectal cancer (HR of 4.3, 1.6-11.4); however, this risk was observed only after the age of 60, 10 years after clinical guidelines recommend starting colonoscopies for the average population. Up to age 60, 0.6% of individuals with PMS2 pathogenic variants were diagnosed with colorectal cancer, similar to 0.4% in the general population but lower than MLH1 (41.0%), MSH2 (17.9%) or MSH6 (4.5%) pathogenic variants.
Conclusion and relevance
The findings underscore the benefits of screening the entire population for MLH1, MSH2 and MSH6 . They also highlight significantly lower cancer risk for those harboring PMS2 pathogenic variants. This study provides data to support tailored surveillance and prevention strategies by gene and highlights the importance of deriving clinical recommendations from relevant populations.
