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Genetic test uncovers risk of inherited breast cancer

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A new gene-editing method can now determine whether certain genetic mutations raise a woman’s risk of breast and ovarian cancer.

The technique helps resolve a long-standing issue in genetic testing, where many patients receive inconclusive results showing “variants of unknown significance” – genetic changes that cannot be clearly linked to cancer risk.

Using the method, researchers have now classified 54 previously unconfirmed variants of the BRCA2 gene, identifying which ones are linked to disease and which are not.

Maria Rossing is clinical research associate professor at the University of Copenhagen’s Department of Clinical Medicine and chief physician at Rigshospitalet.

She said: “If we know a patient has a pathogenic mutation, we can intervene before the cancer has a chance to develop.

“For those already affected by the disease, we can treat them faster and more precisely. In the long run, this will save lives.”

The BRCA2 gene normally helps repair DNA damage. Mutations in this gene are known to increase the risk of several cancers, including breast, ovarian, pancreatic and prostate.

But until now, women carrying uncertain variants have often been unable to access appropriate preventive care.

The technique, developed by the University of Copenhagen and Rigshospitalet, uses CRISPR-Select – a form of gene-editing – to alter DNA in lab-grown cells and track how they respond to chemotherapy drugs.

The classification results are being added to international databases used by clinicians worldwide.

Rossing said: “It’s uncharted territory.

“Until now, we’ve only been able to inform patients that they have a mutation of unknown significance, and treating physicians haven’t been able to use that information in clinical decision-making.”

Women found to carry harmful variants can now be offered more targeted care, such as early screening or preventive surgery.

Rossing added: “When we can provide an accurate diagnosis, we can offer targeted treatment.

“For women who carry a disease-causing variant, we can offer preventive care through early detection and prophylactic surgery.

“But we can’t do that unless we know for sure whether a mutation leads to disease,” Rossing said.

The method combines gene-editing developed at the University of Copenhagen’s Biotech Research and Innovation Center with clinical testing at Rigshospitalet’s Department of Genomic Medicine.

Rossing said: “When researchers or doctors anywhere in the world search for these 54 variants in the databases, they’ll see our classification.

“This has implications far beyond Danish patients,”

Researchers hope the method will be used more widely to help classify thousands of other unknown variants, improving how hereditary cancer risk is assessed worldwide.

Pregnancy

Home blood pressure checks could lower heart risks for new mothers – study

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Home blood pressure checks after hypertensive pregnancy could cut the risk of heart attack, stroke and potentially early death, research suggests.

Women who regularly monitored their blood pressure in the weeks after giving birth, and had doctors tailor their medication if needed, had better functioning arteries nine months later than those who received routine care.

When the medication was adjusted to account for blood pressure changes, the women ended up with less stiff arteries, an effect researchers estimated could reduce the future risk of heart attack or stroke by 10 per cent.

Paul Leeson, professor of cardiovascular medicine who led the study, said the findings suggested that the weeks after birth provided a “powerful and often overlooked opportunity” to protect women’s future health.

“By simply monitoring blood pressure at home, new mothers with hypertensive pregnancies can protect their bodies from future damage,” he said.

High blood pressure, in the form of gestational hypertension or pre-eclampsia, where there are signs of organ damage, affects 5 to 10 per cent of pregnant women.

The condition can damage the mother’s organs and endanger the baby’s life.

Beyond the immediate threat to mother and baby, hypertension in pregnancy can raise the risk of long-term problems, with women three times more likely to develop high blood pressure and twice as likely to have heart disease later in life.

The Oxford team recruited 220 women who developed hypertension in pregnancy. All were on blood pressure medication but were due to reduce their dosage and eventually stop taking the drugs.

In the study, 108 women had standard care in which their medication was reduced based on a few blood pressure checks in the eight weeks after giving birth.

The remaining 112 women used a monitor to check their blood pressure at home each day.

They entered the readings into an app shared with doctors who, if needed, changed their medication day to day, with the aim of giving them better control of their blood pressure.

The new approach led to much better control of the women’s blood pressure, and in tests six to nine months later the women had less stiff arteries.

Stiff arteries are less effective at expanding and contracting, which can drive high blood pressure and ultimately the formation of clots that can block blood vessels and cause heart attacks and strokes.

Trials are now under way to find effective ways of rolling out blood pressure monitoring to women after hypertensive pregnancies. One option is for specialist NHS clinics to deliver the care.

Dr Sonya Babu-Narayan, clinical director at the British Heart Foundation, which funded the work, said the results highlighted a crucial window after birth when paying close attention to blood pressure could help protect women’s heart health for years to come.

“We now look forward to seeing results from larger studies with longer follow-up to see how this might save women’s lives,” she said.

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Researchers teach AI to spot cancer risk by squeezing individual breast cells

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An AI tool could help spot breast cancer risk by analysing how individual breast cells behave when squeezed under stress, research suggests.

Researchers at City of Hope and the University of California, Berkeley, created a microfluidic platform that assesses women’s breast cancer risk at the cellular level.

The platform squeezes individual breast epithelial cells, which line breast tissue, to measure how they deform, recover and behave under stress.

Because more than 90 per cent of women do not have a known genetic predisposition to breast cancer or a family history of the disease, the researchers said the approach could help fill a key gap in risk assessment.

Mark LaBarge, professor in the department of population sciences at City of Hope, said: “For women with a known genetic risk factor for breast cancer, there are things you can do like follow a higher-risk screening protocol. For everybody else, you’re left wondering, ‘Am I at high risk?’

“By translating physical changes in cells into quantifiable data, this tool gives women something tangible to discuss with their doctors, not just risk estimates, but evidence drawn directly from their own cells.”

The researchers developed a machine learning algorithm that identifies and measures cells showing signs of accelerated ageing, generating an individual breast cancer risk score.

They said the platform uses simple electronics that could be easy and affordable to replicate on a large scale.

Lydia Sohn, chair in mechanical engineering at UC Berkeley, said: “Our team isn’t the first to measure the mechanical properties of cells; however, other approaches require advanced imaging technology that’s expensive, cumbersome and has limited availability.

“In contrast, MechanoAge uses computer chips that are simpler than an Apple Watch and ‘RadioShack parts’ that are cheap and easy to assemble, potentially making the device highly scalable.”

About 6 per cent of women who develop breast cancer carry known genetic mutations.

For women outside this group, risk is usually estimated indirectly using population models or measures such as breast density, which can both overestimate and underestimate individual risk.

The researchers said there is currently no non-genetic test that can identify women at higher risk of breast cancer.

Screening mammograms can detect cancer only once it has started to grow, but the MechanoAge platform aims to assess risk earlier by looking for physical changes in individual cells.

Using the platform, the researchers found that breast cells appear to have a “mechanical age” separate from a person’s chronological age, based on how the cells respond to stress.

They said this is the first time mechanical age has been quantified in biological cells.

Sohn said: “We learned that the older the mechanical age, as determined by how cells respond to being squeezed through our microfluidic device, the higher the risk for breast cancer.”

In this type of mechano-node-pore sensing, an electrical current is measured across a liquid-filled channel.

As cells pass through, they disrupt the current, generating measurements about their size and shape. By narrowing parts of the channel, researchers squeeze the cells and then measure how long each one takes to return to its normal shape.

The team found that cells from older women were stiffer and took longer to bounce back after being squeezed.

They also identified a subset of younger women whose cells behaved more like those from older women. These cells came from women with genetic mutations linked to a higher breast cancer risk.

The researchers then refined the algorithm to assign a risk score based on the cells’ measured mechanical and physical properties. They said it successfully identified women with known genetic risks.

The team then used it to compare cells from healthy women, women with a family history of breast cancer, and cells taken from the healthy breast of women with breast cancer in the other breast.

LaBarge said: “With accuracy, we were able to figure out which women were at high risk of breast cancer and which women didn’t seem to be.”

The work grew out of more than 12 years of collaboration between the two labs, combining engineering with cancer and ageing biology.

Sohn said: “It’s a true collaboration. We’ve learned a lot from each other.

LaBarge added: “In my view, this is what happens when you have a real collaboration that develops over a long time. This result is not what we imagined at the beginning.”

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Experimental drug drowns triple-negative breast cancer cells in toxic fats

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An experimental drug slowed triple-negative breast cancer in mice by flooding tumour cells with toxic fats.

Triple-negative breast cancer lacks three common drug targets, making it one of the hardest-to-treat and most aggressive forms of the disease.

The compound, known as DH20931, appears to push cancer cells past their limits by triggering a surge in ceramides, fat-like molecules that place the cells under intense stress until they self-destruct.

In lab experiments, the drug also made standard chemotherapy more effective. When combined with doxorubicin, researchers were able to reduce the dose needed to kill cancer cells by about fivefold.

The drug targets an enzyme known as CerS2 to sharply increase production of these lipids and stress cancer cells. Healthy cells, by contrast, showed lower sensitivity to the drug in lab tests.

While the early results are promising, further preclinical and clinical trials would still be needed to determine the safety and effectiveness of DH20931 in humans.

Satya Narayan, a professor in the University of Florida’s College of Medicine, led the study with an international group of collaborators.

The researchers published their results on human-derived tumours on 21 April and presented their findings on combination therapy at the annual meeting of the American Association for Cancer Research in San Diego.

Narayan likened the drug’s effects to a home’s electrical system handling a power surge.

While healthy cells act like a properly grounded and installed circuit, cancer cells are more like a jumble of mismatched wires and faulty fuses. DH20931 overwhelms cells not with electricity, but with fats.

He said: “When that surge goes into the cancer cells, they cannot handle the amount of power they are getting. The fuses burn out, the cell can’t handle the surge and it dies.”

The compound was developed at the University of Florida in the lab of Sukwong Hong.

Hong, now a professor at the Gwangju Institute of Science and Technology in South Korea, created DH20931 as one of many drug candidates tested for efficacy in Narayan’s lab.

In the study, researchers implanted human triple-negative breast cancer tumours into mice and treated them with DH20931.

The drug significantly slowed tumour growth without causing noticeable weight loss or signs of toxicity in the animals. In separate lab experiments, it also showed activity against other breast cancer subtypes.

In addition to increasing lipid levels, DH20931 triggers a second stress signal by flooding cells with calcium.

Together, these effects disrupt the mitochondria, the structures that produce a cell’s energy, ultimately leading to cell death.

Narayan said: “It does not just follow one pathway but it goes through multiple pathways. It’s a two-hit hypothesis.

“These pathways are common in all breast cancer types and other solid tumours, so we think this drug can be useful not only in triple-negative breast cancer but potentially other cancers as well.”

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