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Comprehensively Testing the Function of Missense Variation in the STK11 Tumour Suppressor
Daniel Zimmerman1,2,3,4, Atina Cote1,2,3, Warren van Loggerenberg1,2,3,4
1The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
Biorxiv : the Preprint Server for Biology
|August 12, 2025
Summary
This study comprehensively analyzed STK11 gene variants, creating a functional map to classify missense variants. This resource aids in understanding Peutz-Jeghers Syndrome and cancer risks, improving clinical variant interpretation.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- The STK11 gene (Serine/Threonine Kinase 11) is a tumor suppressor linked to Peutz-Jeghers Syndrome (PJS) and various cancers.
- A significant majority (over 94%) of clinically observed STK11 missense variants lack definitive classification, hindering clinical actionability.
- Accurate variant classification is crucial for diagnosing PJS and assessing cancer risk associated with STK11 mutations.
Purpose of the Study:
- To systematically assess the functional impact of STK11 missense variants at scale.
- To generate a comprehensive functional map of STK11 variants to aid in clinical classification.
- To provide evidence for interpreting variants of unknown significance (VUS) and predicting future clinical observations.
Main Methods:
- A large-scale mammalian cell-based assay was employed to score 6,026 amino acid substitutions across the full-length STK11 gene.
- Functional scores were generated and validated against existing biochemical data, smaller-scale assays, and pathogenicity annotations.
- The study analyzed the impact of STK11 variants in patient cohorts, including PJS and cancer patients.
Main Results:
- The functional scores demonstrated consistency with known STK11 properties and pathogenicity.
- The study identified distinct patterns for germline STK11 variants in PJS patients diagnosed later in life.
- New evidence was provided for 350 previously annotated STK11 VUS missense variants and approximately 80% of unreported missense variants.
- Somatic STK11 variants in cancer patients showed survival estimates comparable to wild-type STK11.
Conclusions:
- The developed STK11 variant effect map serves as a valuable resource for understanding sequence-structure-function relationships.
- This functional map provides actionable evidence for the interpretation of clinical STK11 missense variants.
- The findings enhance the ability to diagnose PJS and assess cancer risk, particularly for variants of unknown significance.
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