Abstract
PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN mutations, exhibits pleiotropic manifestations, including hamartomas, cancers, and neurodevelopmental disorders, posing challenges in patient management. We hypothesized that mutant PTEN allele-dependent alterations during gastrulation impact PHTS pleiotropism. We generated gastruloids from isogenic human induced pluripotent stem cells with clinically relevant heterozygous PTEN mutations, PTENG132D/WT found in PHTS patients with cancer, hamartoma, and autism spectrum disorder, and PTENM134R/WT associated with cancer-only patients. PTENG132D/WTgastruloids exhibited axial over-elongation driven by AKT hyperactivation, upregulation of Snail, a key regulator of epithelial-to-mesenchymal transition (EMT), and enrichments in mesoderm and endoderm-related gene signatures, compared to those with PTENM134R/WT or PTENWT/WT. Our machine-learning algorithm accurately recognized the over-elongated PTENG132D/WT gastruloids and morphological reversal with AKT inhibitor treatment. Our data suggest a potential link between the mutant PTEN allele-specific early developmental alterations and the clinical outcomes of PHTS, and provide a platform for pathogenic mutation and drug screening.
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Acknowledgements
We would like to thank Washington University Genome Engineering and the hiPSC Core (GEiC) facility for preparing gene-edited human induced pluripotent stem cells (hiPSCs) used in this study. This work was funded, in part, by the Ambrose Monell Foundation PTEN Switch Grant (to C.E.) and the Lisa Dean Moseley Foundation Grant (to C.E. and M.H.). The funders played no role in study design, data collection, analysis, interpretation of data, or the writing of this manuscript. O.E.O. and J.A.V. were Ambrose Monell Cancer Genomic Medicine Fellows (to C.E.). C.E. held the Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic and was an American Cancer Society Clinical Research Professor. The authors thank Tammy Sadler, C.E.’s former lab manager, for her support of this work and language editing. The authors greatly appreciate the support of Dr. Russell Bowler, Dr. John Sedor, and Dr. John O’Toole in acquiring the immediate needs for the revision experiments. The authors also thank the Cleveland Clinic Research Genomic Core and Imaging Core for their services.
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In Memoriam: Charis Eng.
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Onur, O.E., Venegas, J.A., Durmaz, A. et al. Pleiotropic germline PTEN mutations influence gastrulation through dysregulated AKT activation. npj Genom. Med. (2026). https://doi.org/10.1038/s41525-026-00574-z
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DOI: https://doi.org/10.1038/s41525-026-00574-z