Gothenburg, Sweden: Screening people with the rare, inherited cancer-causing condition Li-Fraumeni syndrome (LFS) brings both medical and economic benefits to patients and healthcare systems, according to research to be presented to the annual conference of the European Society of Human Genetics today (Tuesday). The study, the first of its kind to look at these benefits Europe-wide, makes a convincing case for early genetic testing in people known to have the alterations in the TP53 gene that predisposes to LFS, finding that prevention costs per patient are roughly nine times lower than those of treatment. It was performed as part of the EU PREVENTABLE project¹, funded by Horizon Europe and coordinated by Professor Carla Oliveira from the Institute of Research and Innovation in Health, University of Porto, Porto, Portugal.

Ms Marion Rolain, a biomedical researcher and engineer in the Genetics Department at the Centre Hospitalier Universitaire Rouen, Rouen, France who will present the research, says that LFS is one of the most severe hereditary cancer predisposition syndromes. The TP53 gene provides instructions for making a protein that suppresses tumours, keeping cells from growing and dividing too fast or in an uncontrolled way. Children born with an altered TP53 gene are at risk of developing a wide range of tumours at an early age.

The Rouen joint oncogenetics team, comprising researchers from the University Hospital and the Henri Becquerel centre, collected retrospective clinical data from 505 TP53 carriers and 361 non-carrier relatives across seven European countries through nine European Reference Network² expert centres.  Based on standardised French hospital prices, they calculated the costs of each individual’s healthcare pathway. They then compared two groups; those who underwent proactive surveillance with regular screening, and those who received treatment after being diagnosed with cancer.

“Among the 155 TP53 carriers (median age 28) without a prior cancer diagnosis who were included in the preventive group, 18 developed one or more cancers,” says Ms Rolain. “The mean cost of prevention per patient was €6,046.80. We also saw significant improvements in survival in this group. In the 273 patients in the group who had already developed cancer prior to genetic testing, who had a median age of 33, the mean treatment cost was €53,906 per patient. Within this group, 109 patients had early stage and 164 advanced stage disease.”

In LFS, prevention strategies involve the close monitoring of those affected to try to detect the first signs of cancers. The follow-up protocol involves whole-body MRI scans, MRI scans of the brain and, for adults, of the breast, ultrasound examination of the abdomen, and a clinical examination by a specialist.²

The European Reference Network GENTURIS³ has been developing European consensus clinical guidelines for Li-Fraumeni syndrome and other tumour risk syndromes. These centre around the identification of individuals at risk so that they may undergo genetic testing before they develop symptoms. Such individuals are identified through family history or very early onset of LFS-associated cancers, and those with a predisposition to cancer, as in Li-Fraumeni syndrome, can enter surveillance programmes involving regular screening to detect cancers at a very early age.

But despite the increasing use of such preventive surveillance, up until now there has been no large-scale European evidence demonstrating its overall effectiveness and cost. The researchers now intend to continue to analyse their data and publish their results. They hope that their results will be taken up by European health authorities to help strengthen prevention efforts.

“From a clinical perspective, our results were not surprising, since intensive screening should enable earlier cancer detection, generally associated with better clinical outcomes. But what is particularly noteworthy is that we have been able to see this reflected in real-world data across several European countries. And we were also struck by the dramatic difference between prevention and treatment costs.  While further large-scale prospective studies will be needed to confirm our findings, we believe that they are already sufficient to make the case for investing in early genetic testing in tumour risk syndromes,” Ms Rolain says. “We have been able to show that catching cancer early or preventing it altogether is not only better for patients, but also for healthcare systems.”

Chair of the conference, Professor Alexandre Reymond, who was not involved in the research, said:  “With ever-increasing health system costs, it is time to change from a predominantly curative mantra and put more emphasis on prevention. This study is a beautiful example of the clinical and economic benefits of the implementation of personalised health care.”

 (ends)

1 https://preventable.eu/
2. More information on this monitoring can be found at https://rtrs-hub.preventable.eu/)
3. https://www.genturis.eu/

Abstract no. C40.5: Investing in prevention: cost benefits of proactive management in Li-Fraumeni syndrome

Tuesday 16 June, 12:00 hrs, Halls 1 and 2

Gothenburg, Sweden: Understanding why some people stay healthy without developing disease until late in life (have an increased healthspan*), whereas others become infirm at a much younger age has important implications for the health of today’s ageing population. Life expectancy has significantly increased in the last two centuries, but healthspan has not kept pace. Survival into extremely old age (longevity) runs in families and is associated with a delayed onset of multiple chronic health conditions, yet its protective genetic basis remains largely unclear. Most studies to date have looked at the particular genetics of healthy long-lived individuals rather than those of families. However, new research to be presented today (Tuesday) at the annual conference of the European Society of Human Genetics in Gothenburg has revealed that studying long-lived family members can help to identify some of the mechanisms that enable them to have a significantly longer healthspan.

The problem with studying individuals rather than families is that there are so many factors involved in having a long and healthy life. Apart from genetics, socio-economic position, lifestyle, and other behavioural and social factors determine longevity and healthspan, with the result that individuals from a family with an average age at death may still become long-lived; and others may die at well under average age. Presenting the results of the intergenerational ageing study today (Tuesday), Mr Pasquale Putter, a final-year PhD student in Prof. Eline Slagboom’s group at Leiden University Medical Center, Leiden, The Netherlands, explains that their earlier research had shown that middle-aged family members with long-lived parents had a 13 years-later onset of cardiometabolic disease than did their partners with shorter-lived parents. “This made it clear that their longer healthspan was passed down to subsequent generations,” he says.

The researchers scanned the genomes of 212 groups of long-lived sibships (offspring with the same two parents) from the Leiden Longevity Study. They identified four genomic regions at which longevity genes were likely to be found. “This meant that we could restrict our focus to 350 genes rather than around 20 000,” says Mr Putter. After performing further analysis, they found 12 rare protein-altering genetic variants in these regions that might influence longevity.

Previous research has suggested that the CGAS (cyclic GMP-AMP synthase) gene plays a role in the ageing process, and one of these 12 genetic variants mapped to this gene and was identified in two long-lived families. This gene is involved in producing an inflammatory response when DNA is detected within the cell where it does not belong, either in reaction to a viral infection, or when cellular damage has occurred. “It is likely that members of these families had only one active copy of the CGAS gene, rather than two, and that this will have reduced the inflammatory response in their bodies, while still being sufficient to clear infections and repair damage,  thereby contributing to the protective mechanisms that enable extended healthspan and survival,” Mr Putter says.

 “We hope that taking this family approach will help us to untangle some of the environmental factors from those that are truly genetic, particularly those where rare mutations are involved. We have been surprised by the magnitude of the effect of the CGAS mutation in the in vitro experiments we have carried out to date.”

The direct implications of this research for human health have to be explored further, the researchers say, because the role of CGAS depends highly on context. Complete suppression of the CGAS pathway may increase susceptibility to infections and cancers, whereas chronic over-activation can lead to sustained damage caused by inflammation. They are now moving towards in vivo studies to determine whether the changes seen in vitro will translate to similar changes in a whole organism by introducing the CGAS mutation into killifish at the Max Planck Institute for the Biology of Ageing in Cologne, Germany.

“Killifish are the shortest-lived vertebrates, with a natural lifespan of between three to nine months. Using them as a model will enable us to determine whether the mutation contributes to increased lifespan when compared with control groups, and also to investigate its health effects in tissues,” says Mr Putter. “We also intend to follow up on our research by investigating other promising candidate longevity variants that we identified in the Leiden Longevity Study through collaborations with other groups.”

Chair of the conference, Professor Alexandre Reymond, who was not involved in the research, said: “These findings allow our community to zoom in on factors tied to longevity and, more importantly, they point to what maybe are key elements to extend the healthspan of all.”

(ends)

*A person’s healthspan is the number of years they live free from chronic disease and cognitive decline

Abstract no. C37.4: Rare longevity-associated variants, including a reduced-function mutation in cGAS, identified in multigenerational long-lived families

Tuesday 16 June, 11:45 hrs, Congress Hall

Gothenburg, Sweden: Variants in the DHDDS gene cause a severe neurodegenerative condition, characterised by tremors, seizures, coordination and learning difficulties, usually manifesting in early childhood. This Parkinson’s-like condition is extremely rare, and until recently, parents were told that there was nothing that could be done to slow down its progression. But now, researchers from The Netherlands and the US who created ‘mini brain’ models from patients’ own cells to test new therapies, have found not only the mechanism of the disease, but also that a naturally-occurring form of vitamin B3  (nicotinamide mononucleotide, or NMN) holds significant promise in slowing down disease progression.

Presenting the results to the annual conference of the European Society of Human Genetics today, Dr Irena Muffels, a clinical genetics resident at the Wilhemina Children’s Hospital, Utrecht, The Netherlands, described how two parents contacted researchers at the Icahn School of Medicine at Mount Sinai, New York, US, where she was working at the time in the Morava-Kozicz lab. They had been told that the only hope for their two children, who had been diagnosed with DHDDS-related disease, was to wait for researchers to take an interest in the rare disorder.

“But they didn’t want to wait,” says Dr Muffels. “They didn’t want their children to become wheelchair-dependent and unable to take care of themselves due to their movement problems. So they contacted Professor Eva Morava, for whom I was then working. We started creating mini-brains  — tiny blobs of brain tissue grown in the lab from patients' own cells* – thus avoiding the need to take samples directly from the children’s brains.”

The patient-derived mini-brains allowed the researchers to find the DHDDS disease mechanism as well as why it was progressive. After four months, the mini-brains showed clear signs of deterioration, mirroring what happens in real patients. Normal DHDDS helps to produce dolichol, a small lipid ‘anchor’  that carries sugar. In studying the DHDDS mini-brains, the researchers found that this anchor was severely reduced. Sugar also helps build glycans, a kind of antenna that helps proteins perform their correct functions. In the mini-brains, the researchers could see that there were mistakes in the building of these antennae.

Another problem with defective DHDDS is that reduced dolichol affects lipid metabolism as a whole and can lead to significant cholesterol build-up in astrocytes, brain cells involved in neuroprotection. “This accumulation builds over time, and this is why we think the disease progresses,” says Dr Muffels, “since the accumulation of cholesterol leads to mitochondrial dysfunction, leading in turn to reduced energy production.”

The researchers collaborated with the biotech company Perlara to identify potential new therapies by screening FDA-approved drugs and vitamins, and found that NMN was able to rescue a yeast model of DHDDS-related disease. They tested the vitamin in the mini-brains and noticed striking improvements. Since this form of vitamin B3 can be bought without prescription, people started ordering it online before the experiments were completed. “Within a month we had noticed that these patients’ walking improved and that they were more energetic, less shaky, and their movements became more fluid. It really seemed to slow down progression of the disease,” says Dr Muffels.

NMN has been shown to improve molecular mechanisms in muscle cells of patients with mitochondrial disease, a common and devastating paediatric metabolic disorder and is currently it is being tested clinically in these patients. High doses of the vitamin have also been shown to slow progression in Parkinson’s disease patients and reduce symptom burden. Due to the plethora of positive effects that vitamin B3 and NMN can induce at the cellular level, other genetic metabolic disorders that affect energy production in the brain could potentially benefit from the treatment.

”The word about NMN reached more DHDDS patients, and we currently have 12 patients taking it. We recently received funding from CDG UK, the national charity supporting those affected by Congenital Disorders of Glycosylation (CDG), to start an international trial for NMN supplementation in DHDDS-related disease,” says Dr Muffels. ” Patients will take NMN for a year and will be evaluated every three months.  Although I have now left the US, I hope that the Wilhemina Hospital in Utrecht will be one of the official sites and that I may continue to work with these patients.

“There is still a long way to go, but it was encouraging to see how well the creation of the mini-brains helped us mimic the progression of the disease in patients – we could literally see the brains falling apart under the microscope. We were surprised by how fast and how well NMN has worked, and particularly pleased since it is widely available, cheap, and has no known side-effects. In some patients, you couldn’t even see that they were affected by DHDDS disease after treatment. Now, the first four patients are enrolled in the trial and we are looking forward to being able to help them and their families further in the future.”

Chair of the conference Professor Alexandre Reymond, who was not involved in the research, said: “This study is a perfect example of how rapid progress in genetic diagnosis can lead to new treatments for rare diseases. Because rare diseases such as DHDDS affect so few people, it is usually very difficult to get industry interested. It is impressive that a united front of parents, charities and academics were able to find this promising therapy that is also cheap and widely-available."

(ends)

The research was funded by the NIH, the KNAW Ter Meulen Fund, and Cure DHDDS.

*Mini-brain organoids are produced from human skin or blood cells and reprogramme them to become cells that can differentiate into any cell type (pluripotent stem cells), and then into neural stem cells. In the mini brains, different neurons are present, as well as support cells (astrocytes).

Abstract no. C29.2: DHDDS-related juvenile parkinsonismis caused by impaired lipid metabolism, glycosylation, and mitochondrial dysfunction, which can be rescued by NAD⁺treatment.

Monday 15 June, 10h45, Hall C

Gothenburg, Sweden:  New research to be presented today (Monday) at the annual conference of the European Society of Human Genetics shows that a cancer patient’s genetic ancestry can have a significant effect both on how their disease progresses and their survival. In the largest study of its kind, researchers examined nearly 1,900 specific genetic changes in tumours in order to measure whether certain mutations were more common in patients with different historic geographic origins.

Presenting their results, Dr Yixuan He, Assistant Professor of Epidemiology at the University of Texas University Health Science Center, Houston, Texas, US, explained how she worked with her PhD student, Ms Jiawei Tu, to analyse the genetic sequencing data from over 30,000 patients from two large cancer centres – Dana Farber (Boston. Massachusetts) and MD Anderson (Houston). The data covered five different cancers: breast, colorectal, glioma (the most common type of brain cancer), pancreas, and lung.  As well as examining mutations, the researchers also took socioeconomic status and air pollution environmental factors into account to make sure they did not distort the results. They then created a scoring system based on the genetic mutations to try to predict which patients were more likely to die from their cancer, and tested whether combining ancestry information improved the prediction.

Although prediction scoring has been done before, this is the first analysis of its kind to be carried out on such a scale. “Previous studies have been limited to small groups in a single population and in a single tumour,’ says Dr He, “and they have often not taken environmental factors or long-term clinical outcomes into account. By broadening the scope of our study, we hoped to able to show the real, measurable impact of genetic ancestry on cancer genomics and clinical outcomes.”

Results showed dozens of mutations that were significantly more or less common depending on the patient’s ancestry, about half of which can be targeted by existing treatments. The scoring system was able to predict patient survival, particularly so in breast cancer and glioma. When ancestry information was added, the survival prediction became even more accurate, particularly in cancer of the pancreas.

Tumour sequencing is relatively common in modern cancer care, and genetic ancestry can be estimated from those data, so integrating it would not involve additional costs or tests. Environmental factors can also be estimated simply based on where a patient lives. “The challenge of integration would not come from a lack of appropriate technology, but from a workflow that allows the derivation of these important factors from existing routine data collection,” Dr He says. “We are currently collaborating with oncologists in the hope of overcoming these barriers.”

The researchers now intend to expand their analyses to include other cancers and to incorporate additional environmental factors such as smoking and other pollutants – ideally, working with other groups to replicate their findings in other patient cohorts. Although some of their conclusions were already known, they were also able to identify several new associations, for example the over-representation (enrichment) of a gene involved in the control of cell proliferation (CDK6) in African American breast cancer patients, and the loss of SMAD2, another cell proliferation-controlling gene, in American colorectal cancer patients with an admixed ancestry.

“It was very encouraging to see consistent ancestry-related signals replicated between our two different biobanks despite the geographic and population differences between them. By identifying specific genetic markers linked to ancestry we can pinpoint targetable mutations to help doctors use treatments with better survival outcomes. In validating these signals across different populations, we can ensure that a particular treatment is adapted to and effective across a diverse range of patients,” Dr He concludes.

Chair of the conference, Professor Alexandre Reymond, who was not involved in the research, said: “This study shows convincingly the need to assess the disease risks in diverse populations if we are to be able to fully personalise medicine and help the maximum number of patients.”

(ends)

Abstract no. C33.2: Genetic ancestry and environmental differences in somatic alterations and clinical outcomes for five common cancers

Monday 15 June, 10:45 hrs, Rooms H 1 & 2

Gothenburg, Sweden: Oral corticosteroids (OCSs) are widely used and effective in the treatment of chronic inflammatory conditions such as arthritis, asthma, and autoimmune diseases. They work by reducing inflammation, relieving pain, and calming the immune system. However, over one in ten patients develop side effects, particularly if they use steroids over a long period. Until now, it has been difficult to identify those who will react in this way, but results from research to be presented today (Sunday) at the annual conference of the European Society of Human Genetics show that integrating genetic data into steroid prescribing can improve the prediction of risk and thus enable doctors to prescribe them more appropriately.

Dr Deniz Turkmen, a postdoctoral researcher at the University of Exeter AGE Group, Exeter, UK, and colleagues studied data from nearly 38,000 UK Biobank participants who had been prescribed steroids. They calculated how much steroid each one had taken over time; whether higher doses were linked to more side effects; examined whether genetic differences could help explain those who were at risk; and, finally, tested whether adding genetic information improved risk assessment. They found that, in patients treated with steroids, certain genetic variants increased the risk of side effects; CYP3A4 for osteoporosis and CTLA4 for stroke and cataract, among others. “We were also able to show a clear relationship between the dose of steroid and side effects,” says Dr Turkmen. “This precise analysis shows the increased risk associated with long-term treatment”.

Incorporating polygenic risk scores* (PRSs) for osteoporosis enabled the researchers to further improve the steroid risk assessment. This improvement went beyond routinely available factors such as age and sex, and was particularly marked in in younger individuals at the time of their first prescription. “Currently, without efficient prediction methods, clinicians try to reduce risks by using only short courses of steroids, prescribing the lowest possible dose, or switching to alternative steroid-sparing treatments such as biologics. However, biologic treatments are often more expensive and may not be easily accessible to all patients. These strategies may also be insufficient for individuals with chronic conditions who require repeated or long-term steroid treatment. The routine use of genetic information could mean that, in the future, patients at high risk could be identified and given earlier steroid-sparing treatments, or have closer monitoring for side effects,” she says.

Given the widespread use of steroids, large-scale implementation of PRSs in their prescribing will present a major challenge. The most practical application is likely to be targeted to higher risk individuals, and particularly those where steroid use may be longer-term.  The findings also need to be studied in other cohorts to ensure that they are applicable more widely, say the researchers. Larger and ethnically more diverse populations may also enhance predictive performance, since the pharmacogenetic effects observed in the study are consistent with other biological mechanisms that influence steroid metabolism and immune response.

“We anticipated that we would find a clear relationship between dose and adverse outcomes,” says Dr Turkmen, “It was reassuring that the genetic findings involving CYP3A4 and CTLA4 aligned with their roles in steroid metabolism and immune regulation, but the improvement in prediction of osteoporosis when we incorporated polygenic risk scores data was remarkable, especially in younger patients. While single variants had a relatively limited influence on the risk of serious side effects from steroids, adding PRSs for traits such as bone mineral density improved risk prediction. We hope that, in time, greater availability of genetic data at population level will mean that it will be possible to integrate genomics into everyday healthcare and hence into prescribing decisions. That will be a major step on the road to the provision of personalised medicine for all.”

Chair of the conference, Professor Alexandre Reymond, who was not involved in the research, said: “Today we are seeing more and more examples of the predictive value of compounding the risk foreseen for variants that are rare and have a large effect with those of common variants with small effects.”

(ends)

* A polygenic risk score is the assessment of the risk of specific conditions based on the collective influence of many genetic variants in an individual’s genome. 

Abstract no. C27.3: Higher cumulative dose and genetic factors influence oral corticosteroid-related adverse effects in a longitudinal study of 37,000 UK Biobank participants

Sunday 14 June, 17:30 hrs, Hall G3

Gothenburg, Sweden: While non-invasive prenatal testing (NIPT) has revolutionised prenatal diagnostics by allowing the detection of a number of genetic problems in a foetus, it is currently limited and thus misses many genetic causes of abnormalities. But a new technique, to be presented to the annual conference of the European Society of Human Genetics today (Saturday), introduces a technology called non-invasive foetal sequencing (NIFS) that will simultaneously screen almost 23,000 genes, as well as all of the conditions currently captured by NIPT, in pregnancies both with and without a previously-detected foetal anomaly.

Presenting the research, Dr Christopher Whelan, a senior computational scientist working in the laboratory of Dr Michael Talkowski at the Broad Institute of Massachusetts Institute of Technology and Harvard, and at the Center of Genomic Medicine at Massachusetts General Hospital, Boston, MA, USA, says that the new technique was able to identify a very high proportion of the clinically relevant genetic variants that are currently only detectable by invasive genome sequencing (GS). The finding suggests that NIFS may be used as a safer, equally accurate screening tool in all pregnancies, he says.

Most current NIPT methods are low-resolution and focus only a small number of genetic abnormalities, and there is limited standardisation between them. Comprehensive testing of all genes relevant to prenatal diagnostics is only accessible through invasive testing methods. “Currently, many women refuse the invasive sequencing methods -- amniocentesis and chorionic villus sampling (CVS) -- because of the risk to the foetus, related stress, difficulties of access, and cost, even though its diagnostic capacity is high” says Dr Whelan.  “We were trying to develop a test with similar diagnostic value, but without the risks and other downsides.”

The researchers tested NIFS on 565 pregnancies at an average of 17 weeks of gestation. They applied deep cell free foetal DNA (cffDNA) sequencing to the analysis of maternal blood samples, and used advanced computing methods to identify genetic variants across nearly 23,000 genes (the exome*) in each foetus. Checking their findings against those from direct sequencing of the foetus following amniocentesis or CVS allowed them to verify their accuracy; they found that NIFS detected around 95-99% of the genetic variants found by the invasive methods, depending on variant type and inheritance pattern and, importantly, 97.2% of the genetic variants responsible for clinically important conditions in the study. “The test performed really well in capturing all of the clinically relevant variants found by invasive GS that would have been missed by all current non-invasive tests, and accurately genotyping over 97% of them. There were also some unexpected discoveries, such as twin pregnancies with abnormal tissue, and evidence that some mothers had received a bone marrow transplant from a male donor that confounded NIPT results,” says Dr Whelan. “This provided further evidence of the strength of the technique.”

NIFS is estimated to be considerably cheaper than the current gold standard of invasive GS, since it is largely built on capabilities that already exist and are widely available in commercial diagnostic labs and does not require a medical procedure. The technique uses only a slightly greater number of sequencing reads than are needed for invasive GS, and it can be used at an earlier stage in pregnancy than that at which most foetal abnormalities are detectable by imaging. By providing earlier access to genetic information and diagnoses, NIFS can reduce overall costs by allowing more informed management of a pregnancy. The test has already been shown to be accurate in samples from pregnancies as early as 10 weeks gestation, with the proportion of cfDNA in maternal blood that comes from the placenta (the foetal fraction) as low as three percent. “At those fractions, we still saw a very high concordance with clinical GS performed on DNA from invasive testing,” says Dr Whelan.

The researchers now intend to keep improving the capacities of NIFS to be able to identify additional clinically-relevant genetic variants that are not assessed by standard exome sequencing. They are also expanding and scaling their studies in order to enable NIFS screening for all pregnancies in the future.

“While the diagnostic yields and overall performance of the test was not a surprise, it was remarkable that we were able to access and sequence as much of the foetal genome as we did from a simple maternal blood draw during pregnancy. In the future, there is a lot of exciting work happening in the field of prenatal treatment for genetic disease. Together with NIFS, this could be transformative by allowing a treatment to be used at an earlier and more effective stage. NIFS also allows us to begin to capture, months before birth, the clinically relevant information that is currently assessed by newborn screening, allowing early preparation for postnatal management,” says Dr Whelan. “This is an exciting paradigm shift and inflection point for prenatal diagnostics.”

Chair of the conference Professor Alexandre Reymond, who was not involved in the research, said: “Sequencing the entire genome of a foetus without even getting a sample from that foetus is a tour de force. It immediately opens up treatment and prevention opportunities and means that reproductive medicine will be changed forever.”

(ends)

*The exome is the sequence of all the exons in a genome, reflecting the protein-coding portion of a genome.

Funding: The work was funded by research grants from the National Institute of Child Health and Development (NICHD).

Abstract no. PL3.3: Transforming Prenatal Diagnostics: Noninvasive Fetal Exome Sequencing

Saturday 13 June, 17:30 hrs, Hall C