Diagnosis
Genetic test uncovers risk of inherited breast cancer

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

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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