Living implies change. This is what happens to the cells of our bodies as we grow older: they accumulate genetic alterations, most of which are harmless. However, in some specific cases, these mutations can affect certain genes and can lead to the development of cancer. The source of these alterations can be exogenous (e.g., solar radiation, tobacco smoke or some toxic substance) or endogenous (e.g., errors in DNA processing).

Scientists led by ICREA researcher Nria Lpez-Bigas, head of the Biomedical Genomics Laboratory at the Institute for Research in Biomedicine (IRB Barcelona) and Assistant Professor at the Pompeu Fabra University, have characterized for the first time the genetic alterations caused by six therapies widely used for the treatment of cancer (five based on drugs used as chemotherapies, and radiotherapy).

Chemotherapies have revolutionized the treatment of cancer, allowing the survival of large numbers of patients. Some of these therapies kill cancer cells by damaging their DNA. However, these drugs can also harm the healthy cells of the patient, thereby explaining their side effects.

It is important to remember that chemotherapies are highly efficient for the treatment of cancer, says Oriol Pich, first author of the study. But long-term side effects have also been reported in some patients. Studying the DNA mutations that occur in cells as a result of chemotherapies is the first step towards understanding the relationship between these mutations and the long-term side effects of these treatments.

To carry out the study, the Hartwig Medical Foundation in the Netherlands provided the scientists with the sequences of the metastatic tumors of around 3,500 patients and information about the treatments that they received. Using bioinformatics techniques, Lpez-Bigas group has been able to identify a specific pattern of mutations in the metastatic tumors of the patients for each of the most widely used therapiestheir mutational footprint.

Once this footprint has been identified, we can quantify the DNA mutations that have been caused by each kind of chemotherapy, as well as those caused by treatment combinations, explains Lpez-Bigas. We have compared these numbers with the genetic alterations caused by natural endogenous processes. We have calculated that, during treatment, some of these chemotherapies cause DNA mutations at a rate that is between 100 and 1000 times faster than what normally occurs in a cell.

This knowledge will allow the optimization of cancer treatments. The aim is to maximize the beneficial effects of chemotherapies by destroying tumor cells while minimizing the number of mutations caused in the healthy cells of the patients. This would be achieved through a careful combination of dose and treatment duration, says Lpez-Bigas.

Reference

Pich et al. (2019) The mutational footprints of cancer therapies. Nature Genetics. DOI: https://doi.org/10.1038/s41588-019-0525-5

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Genetic Alterations Caused by Cancer Therapies Are Identified - Technology Networks

A rare genetic disorder caused three siblings' blood to flood with fat and turn "milky" white, according to a new report of the unusual case.

The three siblings consisted of one set of fraternal twins (a daughter and son) and an older son, all born to a first-cousin couple in a Pennsylvania Dutch family. In their teens and early 20s, all three siblings experienced mysterious symptoms, including bouts of abdominal pain. They had all been diagnosed with hypertriglyceridemia, a fairly common disorder that causes fatty molecules called triglycerides to build up in the blood.

Now in their 50s, the siblings recently underwent genetic testing and learned that they have a condition that's much more rare, affecting only 1 in every million people, according to the case report, published today (Nov. 18) in the journal Annals of Internal Medicine.

Those with the ultrarare disorder, known as familial chylomicronemia syndrome (FCS), may accumulate more than 1,000 milligrams of triglycerides per deciliter (mg/dL) of blood. For comparison, normal blood levels of the fat should fall below 150 mg/dL, and 500 mg/dL would be considered "very high" in a healthy person, according to the National Institutes of Health.

Indeed, in people with FCS, blood fat levels are so high that the normally crimson fluid turns the color of milk. (FCS is not the only condition that can cause milk-colored blood; the symptom may also appear in people with severe hypertriglyceridemia.)

Related: The Color of Blood: Here Are Nature's Reddest Reds (Photos)

The three siblings had long struggled to keep their triglyceride levels under control and suffered frequent inflammation of the pancreas, also known as pancreatitis a serious condition that can cause abdominal pain, fever and vomiting. At the hospital, the male twin's triglyceride levels reached as high as 5,000 mg/dL, while the other brother's levels peaked at around 6,000 mg/dL. The female twin's triglyceride levels soared highest of all, reaching 7,200 mg/dL at maximum.

The siblings hoped their doctors could help subdue those aggressive symptoms.

To confirm the sibling's rare diagnosis, the doctors looked to their patients' genes. Triglycerides typically build up in the blood due to multiple malfunctioning genes and other related health conditions, such as diabetes or high-blood pressure, according to the Journal of the American Board of Family Medicine. But when doctors probed the siblings' genetic code, the researchers spotted only one mutated gene that was key for breaking down triglycerides in the body.

In healthy people, the gene contains instructions to build a protein called lipoprotein lipase (LPL), which typically coats the blood vessels that run through muscles and fatty tissues in the body, according to the Genetics Home Reference. LPL breaks down fats carried in the blood; without an adequate supply, the siblings' blood plasma ran thick with excess triglycerides.

Related: How to Speak Genetics: A Glossary

Each sibling carried two copies of the mutated LPL gene, meaning both their parents passed down the mutated genetic code to the children, the case report noted. What's more, the particular genetic mutation in the siblings had never been seen before, the authors said. The doctors placed the siblings on a fat-restricted diet, which successfully stabilized their triglyceride levels and quelled their bouts of pancreatitis. Sometimes, when triglyceride levels spike, doctors must manually replace the fat-filled blood of their patients with healthy blood from donors, Live Science previously reported. Thankfully, the siblings' condition could be curtained with diet alone.

Originally published on Live Science.

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A Rare Genetic Disorder Turned These Siblings' Blood 'Milky' White - Livescience.com

A devastating fungal disease, the cause of ash dieback, is on course to decimate Europes ash trees, with 70 million in the UK currently expected to perish over the coming years, costing the economy an estimated 15bn.

But in some pockets of woodland, resistance to the sickness has been detected, offering a glimmer of hope that ash trees will not be permanently erased from the landscape.

Scientists sequenced whole genomic DNA from 1,250 ash trees in 31 different areas in order to identify the inherited genes associated with ash dieback resistance.

Sharing the full story, not just the headlines

The study, published in the journal Nature Ecology & Evolution, shows resistance is controlled by several genes, offering hope survivors could be used to restore diseased woodlands, either by natural regeneration or selective breeding.

Professor Richard Nichols, author of the study from Queen Mary University of London, said: We found that the genetics behind ash dieback resistance resembled other characteristics like human height, where the trait is controlled by many different genes working together, rather than one specific gene.

Overall winner of the competition

Csaba Daroczi/NPOTY 2019

Winner in the Underwater category

Alexey Zozulya/NPOTY 2019

Finalist in the Mammals category

Jose Juan Hernandez/NPOTY 2019

Finalist in the Man and Nature category

Tom Svensson/NPOTY 2019

Finalist in the Mammals category

Marcio Cabral/NPOTY 2019

Winner of the Youth category

Giacomo Redaelli/NPOTY 2019

Finalist in the Man and Nature category

Britta Jaschinski/NPOTY 2019

Finalist in the Other Animals category

Wei Fu/NPOTY 2019

Finalist in the Landscapes category

Brandon Yoshizawa/NPOTY 2019

Finalist in the Man and Nature category

Pedro Narra/NPOTY 2019

Overall winner of the competition

Csaba Daroczi/NPOTY 2019

Winner in the Underwater category

Alexey Zozulya/NPOTY 2019

Finalist in the Mammals category

Jose Juan Hernandez/NPOTY 2019

Finalist in the Man and Nature category

Tom Svensson/NPOTY 2019

Finalist in the Mammals category

Marcio Cabral/NPOTY 2019

Winner of the Youth category

Giacomo Redaelli/NPOTY 2019

Finalist in the Man and Nature category

Britta Jaschinski/NPOTY 2019

Finalist in the Other Animals category

Wei Fu/NPOTY 2019

Finalist in the Landscapes category

Brandon Yoshizawa/NPOTY 2019

Finalist in the Man and Nature category

Pedro Narra/NPOTY 2019

Now we have established which genes are important for resistance we can predict which trees will survive ash dieback. This will help identify susceptible trees that need to be removed from woodlands, and provide the foundations for breeding more resistant trees in future.

Samples were collected from ash trees in a Forest Research mass screening trial, which comprises 150,000 trees across 14 sites in southeast England.

The researchers screened for resistance genes using a rapid approach where the DNA of diseased and unaffected trees was separated.

Many of the genes found to be associated with ash dieback resistance were similar to those previously shown to be involved in disease or pathogen responses in other species.

Ash dieback is a major threat to the UK landscape. According to the Woodland Trust, the effects will be staggering.

It will change the landscape forever and threaten many species which rely on ash, the trust has warned.

The fungus Hymenoscyphus fraxineusaffects ash trees of any age and in the UK between 70 and 95 per cent of ash trees are expected to succumb.

The 15bn economic impact is expected to be greater than that of the 2001 foot-and-mouth disease outbreak which led to more than 6 million cattle and sheep being exterminated, according to an assessment this year by a team from Oxford University.

The predicted costs include clearing up dead and dying trees, but also lost benefits provided by the trees, including water and air purification and carbon sequestration.

The loss of these services is expected to be the biggest cost to society, while millions of ash trees also line Britains roads and urban areas, and clearing up dangerous trees will cost billions of pounds.

The disease has spread throughout Europes ash populations, and was first recorded in the UK in 2012.

Professor Richard Buggs, senior research leader in plant health at the Royal Botanic Gardens, Kew and lead author of the paper, said: There is no cure for ash dieback and it threatens to kill over half of the 90 million ash trees in the UK. This will have huge impacts on the British landscape.

Our new findings of the genetic basis of natural resistance found in a small minority of British ash trees help us to predict how ash populations will evolve under ash dieback. While many ash trees will die, our findings are encouraging from a long-term perspective and reassure us that ash woodlands will one day flourish again.

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Ash dieback: Genetic resistance offers new hope over unstoppable disease expected to kill 70 per cent of species - The Independent

For most patients,sudden cardiac death iscompletely unexpected, according toDr. Amit Khera, a cardiologist at Massachusetts General Hospital.

Its always particularly devastating because many dont have prior symptoms. Their first symptom is actually dropping dead, Khera said. The question is can we find these people before something really bad happens?

Many scientists, including Khera, theorizedthat one way to find people who might suffer these sudden cardiac deaths fatal events related to an abrupt cardiovascular failure could betheir genetics.

We always had a hunch that maybe there was something in their DNA that predisposed them to this tragedy, he said.

Now, he and his colleagues believe theyve found 14 different gene variants, spread across seven genes that may put their carriers at greater risk for sudden heart death.

The researchers made this discovery by sequencingthe genes of 600 people who died from sudden cardiac death and600 people of the same age whowere healthy. Khera said they focused on 49 genesalreadyknown to be important for cardiovascular disease.

These genes contribute to any of the four major causes [for sudden cardiac death], he said. Sometimes its a weak heart and the pumping function is not quite right. The second is a heart attack. The third is a problem with the hearts rhythm. The last is a tear in a major blood vessel.

After a geneticist on the team analyzed the genetic data, Khera said 14 different versions of 7 genes stood out.

These 14 variants were found in 15 people. Whats really striking is that all 15 people were sudden cardiac death cases and zero were [healthy], he explained.

The team reported their findings Saturday in the Journal of the American College of Cardiology.

After identifying the specific gene variants, theresearchers looked ata larger database of 4,000 individuals. They found that about 1% of the population without a history of heart disease carries similar mutations in one of the 49 genes scientists believe are critical to heart health.

Its a really small percent of people, but an important percent," said Khera. "These people are predisposed to sudden cardiac death, and if we can find them then we have tools to prevent disease onset.

Carrying one of those mutations doesnt mean a person is certain to suffer from sudden cardiac death, Khera says. But his analysis suggests they do make the event three times more likely over a period of 15 years.

In most cases, doctors saysudden cardiac death arises from preventable causes.

Most of the gene variations underlying [sudden cardiac death] are related to the electrical rhythm of the heart going chaotic or haywire," said Dr. Eric Topol, vice president of Scripps Research and a cardiologist who did not work on the study.

"There are many ways you can prevent this occurrence if you know a person has a high risk mutation, Topol said. Medications or a device like a defibrillator or pacemaker can fix the underlying problem.

There are likely many more mutations that increase the risk for sudden cardiac death.

The more we find of these, the more confident we are that they are the real deal, the better we will, in the future, be at preventing these catastrophes, Topol said. So, I think this is really important work.

And not every sudden cardiac death strikes healthy individuals with no previous history of heart disease, Khera added.

Of course, important lifestyle factors play a role, like smoking over the course of a lifetime or not well controlled blood pressure, he said.

But often, families and friends of those who die from sudden cardiac death dont get a reason for why it happened.

The DNA can provide an explanation as to why this happened, Khera said. And even more importantly, this persons family members may also have the gene variant, and if they know about it then they can take preventative measures.

Editor's note: There are many mutations in the 49 genes researchers looked at in this study that may increase the risk of sudden cardiac death. Those "disease-causing" mutations occur in roughly 1% of the population, according to the research. The study focused on 14 of them.

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Finding Mutations On These 49 Genes May Help Prevent Sudden Cardiac Death - WBUR

"It has a whole bunch of other things surrounding it, but it creates depressive symptoms."

According to SANE Australia, up to 4 per cent of Australians will develop BPD at some point in their life, with the symptoms usually manifesting in late adolescence.

Sufferers have trouble managing their emotions and impulses, and can also struggle to maintain a stable self-image.

The causes of BPD are not well understood, although they are believed to be a combination of biological and lifestyle factors.

Ms Collett said despite her diagnosis being relatively simple compared to other mental health issues, it was "frustrating" that there still wasnt a clear diagnosis and treatment for many sufferers.

Its hoped that new research from QIMR Berghofer Medical Research Institute could help change that, with scientists there identifying key areas on the human genome with direct links to depressive symptoms.

Senior study investigator Professor Eske Derks said the research uncovered seven distinct regions on the human genome with links to symptoms.

"We identified, for the first time, three genetic regions related to sleep problems, two for anhedonia [a loss of interest or pleasure in life], one related to changes in appetite, and one for depressed mood," Professor Derks said.

Overall, about one in 11 people, or 9 per cent of Australians, reported having depression or depressed feelings in 2014-15, according to figures from the Australian Bureau of Statistics.

The QIMR findings provide insight into why the symptoms of depression can vary hugely between patients, and they point the way to more targeted therapies.

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"In some patients, depression will manifest as a reduced appetite, while for others, there will be increased appetite," Professor Derks said.

"So normally if youre looking for the genetic risk factors for depression, you tend to collapse all of these symptoms together, even though they can be quite different from patient to patient."

Professor Derks said being able to accurately assess exactly what genes were in play for individual patients meant they would be able to get tailored treatment instead of the current method of "trial and error", where patients are prescribed the most common medication and then put on other drugs if that fails.

Ms Collett said it would be a comfort going forward to have a more certain diagnosis.

"Im naturally curious about my own health situation, so it would be really good to know the underlying reason why I have it. Was it genetics? Was it something that happened when I was a kid? Who knows?" she said.

The study, which examined genetic data and self-reported symptoms from 150,000 people from the UK Biobank, has been published in the journal Psychological Medicine.

Stuart Layt covers health, science and technology for the Brisbane Times. He was formerly the Queensland political reporter for AAP.

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Clear link between genetics and depressive symptoms uncovered - The Age