Case study: Identification of genomic modifiers of PTEN-related phenotypes
Key facts
Research category: Natural history/translational medicine
Lead researcher: Professor Charis Eng, MD PhD
Institution: Genomic Medicine Institute, Cleveland Clinic, USA
Project start: September 2020 Expected completion: June 2025
The whole of PTEN Research Foundation were greatly saddened to hear of death of Prof Charis Eng in August 2024. The majority of this work has been completed and the results will be published in due course.
Project goals
To identify genomic modifiers predictive of clinical outcomes in PTEN mutation carriers, by performing whole genome sequencing (WGS) on a population of extensively phenotyped individuals with PHTS. Ultimately, it is hoped that this approach may provide a framework for stratifying PTEN-related disease risk at the individual level, as a basis for precision healthcare.
Rationale
Studies have shown that individuals with the same PTEN mutation can display widely different clinical manifestations, even within a family. Thus, it remains impossible to predict at an individual level precisely which PTEN variant carrier will develop which symptom(s). How variants in one gene contribute to such disparate disorders, even in people with identical PTEN variants, remains poorly understood. Earlier, PTEN Research-funded work conducted by Professor Eng and her team, have led them to hypothesise that PHTS aetiology is not driven by just the PTEN gene variant, but may involve complex gene-gene interactions and that constitutive non-coding genomic modifiers in particular may modulate a major subset of clinical phenotypic manifestations in PHTS.
Study design
Whole genome sequencing will be performed on a well-characterised group of individuals with PHTS who have constitutive pathogenic, or likely pathogenic, variants in PTEN, identified from the Cleveland Clinic prospective cohort for Cowden Syndrome and Bannayan-Riley-Ruvalcaba syndrome, and the Rare Disease Clinical Research Networks cohort. These data will then be interrogated in a variety of ways to identify if and what genetic variations in the genome of people with PHTS lead to disparate clinical outcomes.
Anticipated outcomes of this work
It is hoped that this research will lead to the identification of genetic markers that may be used to better inform the clinical outcome of individuals with PHTS, to optimise surveillance, and to develop medical management leading to precise risk stratification and biomarker-informed treatments and prevention. In addition, this rich and detailed dataset will be invaluable for future research to better understand PHTS and identify new and novel therapeutics.