Image credit: Shannon Gunn / Wellcome Sanger Institute

Categories: Sanger Science25 August 2026

One gene, many outcomes: Understanding variable cancer risk in PTEN hamartoma tumour syndrome

By Rachael Smith, Media and Communications Manager, Wellcome Sanger Institute

Changes in the PTEN gene, that causes PTEN hamartoma tumour syndrome (PHTS), can lead to a range of different manifestations that vary from person to person, including an increased risk of certain cancers. A new project aims to understand why some tissues in people with PHTS become cancerous, and if there is a way of identifying individuals with PTEN variants who are most at risk.

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Not all genetic conditions follow a simple script. With changes in the PTEN gene – a tumour suppressor gene that normally acts as a brake on cell growth – every cell in the body carries the same alteration from birth. Yet what happens next can be very different from person to person. Some individuals develop multiple cancers, while others may never develop cancer at all; in addition, people can also develop non-cancerous (benign) tumours.

Part of the answer lies in a second layer of biology. Although in some individuals one copy of the PTEN gene is altered from birth, cells often need to lose the remaining working copy before they begin to grow in an uncontrolled way. This can happen by chance in individual cells over time – like a second fault in a system that was already vulnerable. But even that does not fully explain the remarkable variability seen in people with PTEN variants.

So why does the same genetic starting point lead to such different outcomes? And how can genomics help us understand – and eventually predict – what happens next? A new project led by researchers at the Wellcome Sanger Institute aims to understand how inherited PTEN changes influence the growth of cells across different tissues, and why this genetic change leads to cancer development in some tissues but not others. The researchers hope that this work will help inform future approaches for screening, enable the identification of those at highest risk of cancer, and support early detection of tumours.

What is PTEN hamartoma tumour syndrome?

PTEN hamartoma tumour syndrome (PHTS) is a rare genetic condition that causes increased risk for certain cancers and benign growths. This includes skin hamartomas and other non-cancerous tumours, as well as a range of other symptoms including possible neurodevelopmental conditions and anomalies in blood vessels or lymph nodes. Some individuals with changes in the PTEN gene also have a larger head circumference, known as macrocephaly.

PHTS is caused by changes in the PTEN gene and is most commonly inherited from a parent, although they can also occur early in human development. It follows an autosomal dominant inheritance pattern, meaning only one altered copy is needed to increase your risk. With only one working copy of this tumour suppressor gene, cells are more prone to overgrowth, leading to the possibility of them developing into hamartomas or cancer.

No two individuals with PHTS are alike, meaning that care is tailored to each individual’s needs. PHTS increases the risk of certain cancers before the age of 60 years, and this risk is substantially higher in women, who have around a 77 per cent risk of developing PHTS-associated cancers, compared with men, where the risk is approximately 18 per cent.1

Specifically, cancer risk is higher in certain tissues – with an estimated 65 per cent risk of developing female breast cancer, around a 14 per cent risk of endometrial cancer, and about a 14 per cent risk of thyroid cancer.1 There are also increased risks of melanoma, colorectal, and renal cancers.1

Pam's experience

Pam, 61, was diagnosed with Cowden syndrome with a PTEN variant – the most common type of PHTS – in 2010 when she was 46 years old. The eldest of five siblings, she was initially referred to a geneticist after two of her sisters developed breast cancer within a year of each other.

“During the appointment with the geneticist, he asked me if I struggled to find hats that fit. So, me and my partner looked at each other, started laughing, and were like, ‘No, but what has that got to do with the fact that I might be at risk of breast cancer?’ And he said, ‘Well looking at your history, I don't think you've got BRCA1- or BRCA2-associated variants, I think you’ve got something much rarer called Cowden syndrome.’

One blood test and three months later, a diagnosis was confirmed. I knew this meant that my family could also get tested, which led to three more positive test results. It does explain a lot of the cancers and other conditions present throughout our family history, and is probably what caused the haemangioma tumour in my wrist, which formed from blood vessels, when I was 12.

My life since then has been an endless stream of hospital appointments and screenings.

I’ve had my thyroid removed because of nodules and a total hysterectomy. I have had a prophylactic preventative mastectomy, and routine testing following the surgery, found pre-cancerous cells. I’ve also had skin cancer, and I have hyperpolyposis, with a thousand plus polyps (growths) in my colon, and my stomach is carpeted with them. A geneticist once told me that I would have to always be on the lookout because I am the person most likely to notice the first signs of a new medical issue.

The impact on my daily life is huge, but the hardest part isn’t just the surgeries; it’s the mental toll and the impact on my family. It turned out that my mother was the carrier, and the guilt she felt was immense. There was a lot of anger towards me for getting diagnosed as my family felt it may have been better for them to continue dealing with the medical issues without knowing the reason.

It’s been devastating to watch my siblings go through this; my youngest sister and brother both died at the exact same age, 49 years and 4 months, from complications linked to PTEN.

As it impacts everyone differently, it’s hard not to look at how it’s affecting other people and worry if I’ve got that coming in my future.

Also, because it’s an invisible disease, people look at me and think I’m fine, but they don't see the monthly turmoil or the anxiety of having to be my own specialist because so many doctors don’t know about my condition – one even had to Google it while I was sitting right in front of them. We need better education for medical professionals, so they understand and recognise Cowden syndrome as an invisible disease rather than a one-size-fits-all condition, and know how to treat it. At one point, the geneticist I was working with mentioned setting up a dedicated PTEN clinic in the North East, but it’s not happened yet. But having a place like that, with specialist support, would make such a difference.

For now, I’ve found ways to cope. After spending 20 years on antidepressants, now I focus on holistic healing, sound baths, meditation, and nature to manage the anxiety. I also volunteer with Age UK and help with projects about PHTS to turn my experience into something that helps others.”

In the North East, where I’m from, we have a ‘crack on’ attitude, so, I put a smile on my face, I look after my partner and my rescue dog, and I refuse to let this syndrome define who I am.

Pam and other patients living with PHTS are often left without answers to what the future looks like. Now, a new research project is attempting to understand more about the condition at a molecular level to try to address some of the unanswered questions surrounding PHTS.

How can genomics help?

While the genetic change that causes PHTS is known, it is still unclear why it causes tumours in these specific tissues. However, thanks to new funding from PTEN Research, Dr Raheleh Rahbari, Group Leader, and Dr Joseph Christopher, Clinician Scientist, at the Wellcome Sanger, are attempting to better understand this.

The new project, titled ‘RECCE-PTEN: Researching Early Cancer by quantifying clone dynamics in individuals with germline PTEN variants’, is a pilot study that aims to unravel tissue-specific tumour development and build a biobank of samples to better understand PHTS. By comparing patient tissues that develop tumours with those that remain healthy, the team hopes to uncover what drives some cells to become cancerous and identify factors that protect other tissues, guiding new understanding and hopefully, avenues for future biomarkers. In the future, the researchers also hope this could help inform early cancer detection plans, along with new treatments to possibly prevent cancer from developing at all.

“With this research project, we are aiming to understand more about PHTS in a way that can hopefully open new clinical avenues in the future for patients and their families. We are incredibly grateful to the patients and their families for their support and their involvement in this project – the first of its kind – and we hope to continue to work together to build a resource that can have wide-reaching impacts for the community in the years to come.”

Dr Raheleh Rahbari,
Project co-lead and Group Leader at the Wellcome Sanger Institute

As part of this pilot project, the team is collaborating with the PTEN National Registry to develop a tissue donation network for the patient community, building a biobank of samples that scientists all around the world can use to further research. This biobank resource could help give a comprehensive overview of the condition from a genetic level and help identify if there are shared biomarkers that could be used to identify those most at risk.

“PTEN Research recognises the need to better characterise the molecular changes underlying early cancer development and the importance of these data in informing future non-invasive monitoring strategies for individuals with PHTS. We are excited to support this innovative project led by Drs Rahbari and Christopher, which aims to advance understanding of PHTS-associated cancers and create a valuable tissue resource for future studies, ultimately benefiting individuals and families with PHTS.”

Thomas Pepper,
Chief Executive and Director of Clinical Development, PTEN Research

How will the team uncover genetic insights?

This project will use ultra-sensitive DNA sequencing and precision tissue analysis, including using lasers to cut out tiny sections of tissue in a process known as laser capture microdissection, to investigate the earliest genetic changes associated with cancer in people with PHTS.

PTEN genetic changes can be difficult to pick up with regular, large-scale, short-read sequencing. Therefore, it requires the use of nanorate sequencing, or NanoSeq – a tool developed at the Sanger Institute that makes it possible to study changes that happen in a small number of cells whilst maintaining a high level of accuracy.

This tool, along with the precision of laser capture microdissection, will allow the team to conduct multi-omic analysis of samples provided by patients. A multi-omics approach captures the genomic information, held in the genome, the transcriptome (RNA expression), and methylome (information on the modifications that turn genes on or off in the metabolome (data on what metabolites are produced)). This creates a static blueprint of the cell to understand tissue-specific cancer development.

Along with scientific expertise, the Sanger Institute has established technical and analytical pipelines to process NanoSeq data and has the infrastructure and bioinformatic capacity to analyse the data robustly.

“By diving into the genomic detail of PHTS, this unique project will hopefully uncover actionable insights that could help understand cancer risk and shape future screening programmes for those living with the condition. This would not be possible without the combination of technical sensitivity, analytic expertise, and experience in studying human genetic changes that is found at the Sanger Institute.”

Dr Joseph Christopher,
Academic Clinical Lecturer and Project co-lead at the Wellcome Sanger Institute

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Looking to the future

The team hope this approach may eventually provide a framework for studying how inherited genetic changes influence the evolution of cells in other cancer predisposition conditions, helping to bring together impacted communities and researchers to drive forward research and hopefully find new avenues for those impacted.

“Understanding how PTEN variants reshape somatic evolution across different tissues could provide important insights not only into PHTS-associated cancers, but more broadly into why some tissues become vulnerable to cancer transformation, while others don’t. We hope this work will help build a framework for understanding how genetic background influences cancer risk and tumour development across the human body, while also creating resources that can directly benefit patients and families living with PHTS.”

Dr Raheleh Rahbari,
Project co-lead and Group Leader at the Wellcome Sanger Institute

“More research is absolutely necessary to be able to detect the condition and the related cancers earlier. I do wonder if the health outcomes for my siblings and I would have been different if we had been diagnosed and screened much earlier in life. Also, research that leads to understanding why the syndrome affects family members so differently could answer so many questions for myself and the rest of the PTEN community. Specifically, things like why one of my sisters lost her sight, and another developed a rare, fatal brain tumour, while I face a different set of complications. We are often left without understanding what to expect in the future, and research can help bridge this gap and educate medical professionals, leading to more answers and better care. We deserve that.”

Pam,
who is living with Cowden syndrome

For more information, or to get involved in this study, please email Dr Joseph Christopher (jc27@sanger.ac.uk) or Dr Raheleh Rahbari (rr11@sanger.ac.uk).

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Reference

  1. Hendricks, N. Hoogerbrugge, AR. Mensenkamp, et al. (2023) ‘Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome.’ Journal of the National Cancer Institute. 115: 93–103. DOI: 10.1093/jnci/djac188.

Additional information

PTEN Research is a UK-registered charity that is funding this new research project. They fund and facilitate research that will lead to new and better treatments for PHTS, a rare condition which currently has no health authority approved therapies. They do this by funding research projects and bringing together a global network of PHTS focussed experts and other key partners. To find out about grant funding opportunities visit: ptenresearch.org/for-researchers-and-professionals/apply-for-research-funding/.

PTEN UK & Ireland is a charity that is working to improve the lives of patients, parents and carers of all ages, in the United Kingdom and Ireland, who are affected by PTEN genetic alterations, including PTEN Hamartoma Tumour Syndrome (PHTS), Cowden Syndrome (CS), or Bannayan-Riley-Ruvalcaba Syndrome (BRRS). For more information, visit: ptenuki.org/

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