Assessing the outcomes of cancer in PHTS
Introduction
A key clinical feature of PHTS is the increased lifetime cancer risk, particularly of breast, thyroid, endometrial, renal, colorectal cancer and melanoma.
Current published management guidelines for PHTS recommend a comprehensive program of age-appropriate cancer surveillance to support early identification. Recently, international consensus guidelines for the surveillance and management of cancer and overgrowth in PHTS have been published, aiming at improving care for affected individuals and families.
At present, cancer treatment for people with PHTS is similar to that for individuals with sporadic cancers. Until recently, it was unknown whether the outcome of cancer treatment in individuals with PHTS differed from the general population.
Better understanding of the treatment and cancer outcomes in people with PHTS, as well as the mechanisms underlying the increased cancer risk in PHTS are supported by the following two grants.
Project 1 key facts
Project title: Cancer prognosis and treatment of PHTS patients
Type of study: Natural history/translational medicine
Lead researcher: Prof Nicoline Hoogerbrugge
Institution: Radboud University Medical Center, Nijmegen, Netherlands
Project start: January 2020 Completed: September 2025
Project 1 goals
To assess the cancer-specific and age-specific prognosis for people with PHTS, and to explore the effect of different cancer treatments on prognosis.
Project 1 overview
This retrospective study is built upon an earlier project funded by PTEN Research, which established a European PHTS cohort from over 20 centres of PHTS expertise in Europe. The cohort was recruited via the European Reference Network (ERN) GENTURIS, a collaboration amongst expert clinical centres for rare genetic tumour risk syndromes, chaired by Dr Hoogerbrugge.
For this study, over 500 people with PHTS who were diagnosed with cancer were identified. The prognosis of these individuals was assessed, with a focus on breast and thyroid cancer. Data from after the diagnosis of cancer was collected on vital status, cancer treatment and surveillance, and cancer recurrences and metastases.
Outcomes
This project has now been completed.
The key result showed that the prognosis of PHTS-related cancers was no worse than for comparable cancers in the general population (sporadic cancers) and that standard cancer treatment is appropriate for individuals with PHTS with cancer.
The research also showed that lifestyle among individuals with PHTS is important as a healthier lifestyle (higher physical activity, lower alcohol consumption and tobacco smoking) could potentially decrease breast cancer risk in a similar way as for the general population.
Ultimately, it is hoped that this research will contribute to more informed clinical decision making for those managing people with PHTS who develop cancer, resulting in better treatment and improved outcomes.
The following publications have resulted from work associated with this grant:
- A review on age‐related cancer risks in PTEN hamartoma tumor syndrome
- Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN Hamartoma Tumour Syndrome and literature review
- Cancer risks by sex and variant type in PTEN Hamartoma Tumor Syndrome
- Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort
- Lifestyle factors and breast cancer risk in females with PTEN Hamartoma Tumor Syndrome (PHTS)
- Histopathological phenotyping of cancers in PTEN Hamartoma Tumor Syndrome for improved recognition: A single‐center study
- Cancer prognosis and treatment results in patients with PTEN Hamartoma Tumor
Syndrome (PHTS) – a European cohort study - The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)
Project 2 key facts
Project title: Researching Early Cancer by quantifying ClonE dynamics in individuals with germline PTEN variants (RECCE-PTEN)
Type of study: Basic research
Lead researchers: Dr Raheleh Rahbari1, Dr Joseph Christopher1,2
Institution: 1Wellcome Sanger Institute, 2University of Cambridge
Project start: February 2026 Expected completion: February 2028
Project 2 goals
There are no effective strategies for early detection or prevention of malignancy in PHTS beyond routine clinical surveillance. A challenge in managing cancer risk in PHTS is distinguishing between benign overgrowth and malignant transformation.
This study aims to improve our understanding of the processes underlying the increased cancer risk in PHTS by discovering driver genes and pathways under positive selection in tissues from individuals with PHTS.
Project 2 overview
This study will use a high-accuracy sequencing method and multi-omic approaches to characterise somatic mutations in normal tissues from individuals with PHTS to investigate how constitutional loss of PTEN function in PHTS alters selective pressures on somatic mutations. The researchers are working closely with the UK PHTS Registry.
Anticipated outcomes
Characterisation of the early changes resulting in malignancy could, if further validated in future larger studies, help identify potential early cancer biomarkers and support identification of targets for cancer prevention. It could also help us understand why only some tissues have an increased cancer risk in PHTS.
In addition, the project aims to establish a sustainable and scalable UK research network for study participants and their families, with one of its key objectives being to commence a long-term biobank of fresh frozen tissue from consenting individuals with PHTS.
The data generated in the study will be shared via research repositories such as the European Genome-phenome Archive (EGA) so it can be used by other researchers.