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Population-based Characterization of PTEN Hamartoma Tumor Syndrome
Ying Ni1, Gideon Idumah1, Chloe Bautista1
1Cleveland Clinic.
Research Square
|February 6, 2026
Summary
PTEN hamartoma tumor syndrome (PHTS) is more common and diverse than previously thought. Population-scale genomics reveals PHTS is underdiagnosed, affecting approximately 1 in 7500 individuals and linked to higher cancer risk.
Area of Science:
- Genomics
- Oncology
- Medical Genetics
Background:
- PTEN hamartoma tumor syndrome (PHTS) is a genetic disorder linked to germline PTEN variants, predisposing individuals to cancer.
- The full clinical spectrum and prevalence of PHTS are poorly understood due to reliance on limited, highly selected patient cohorts.
- PHTS is often underrecognized and its prevalence underestimated in the general population.
Purpose of the Study:
- To determine the prevalence and clinical spectrum of PHTS in a large, diverse population.
- To assess cancer risk and age of diagnosis in individuals with PTEN variants compared to other genetic profiles.
- To identify novel phenotypic associations related to PTEN variants.
Main Methods:
- Analysis of genomic and electronic health record data from 414,830 participants in the All of Us Research Program.
- Identification of individuals with pathogenic or likely pathogenic PTEN variants.
- Comparison of cancer prevalence and age at diagnosis between PTEN variant carriers, carriers of other cancer-related gene variants, and noncarriers.
Main Results:
- Identified 55 individuals with pathogenic PTEN variants, with most lacking a prior PHTS diagnosis, indicating significant underrecognition.
- Estimated PHTS prevalence at ~1/7500 in the US cohort, approximately 26-fold higher than historical estimates.
- PTEN variant carriers showed the highest cancer prevalence and significantly earlier ages at first cancer diagnosis.
- Observed broader systemic involvement beyond typical overgrowth features, including adenotonsillar hypertrophy, sleep apnea, acanthosis nigricans, and extreme obesity.
Conclusions:
- PHTS is significantly more prevalent and clinically heterogeneous than currently recognized.
- Population-scale genomic data are crucial for comprehensive characterization and earlier detection of PHTS.
- Current clinical practices may underestimate the burden and impact of PHTS, highlighting the need for increased awareness and diagnostic efforts.
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