A type of low-grade but sometimes lethal brain tumour in children has been found in many cases to contain an unusual mutation that may help to classify, diagnose and guide the treatment of the tumours, report scientists at Dana-Farber Cancer Institute.
The researchers led a study of pediatric low-grade gliomas, samples of which were collected through an international consortium organised by brain tumour specialists at Dana-Farber/Children’s Hospital Cancer Center.
Low-grade gliomas are the most common type of pediatric brain tumours, diagnosed in about 1,000 young patients annually in the United States. There are about 30 distinct types of these tumours, which arise from specialized cells called glia in the brain. Low-grade gliomas are generally slow-growing, said Keith Ligon, MD, PhD, a senior author of the study, but they behave unpredictably and can be life-threatening.
The investigators focused on diffuse low-grade gliomas, so-called because they lack a tumour mass but spread throughout the brain. As a result, diffuse gliomas often recur after surgery and are more likely to evolve into lethal glioblastomas than are non-diffuse low-grade tumours. ‘Many of these patients do well, but it’s hard to generalise as the tumours are difficult to diagnose and study because without better tools pathologists can’t name them consistently,’ explained Ligon, who in addition to being a researcher is also a neuropathologist. The research was undertaken in hopes of identifying a common genetic alteration that could be used to better define and design treatments for them.
The researchers analysed DNA from 45 tissue samples collected from seven institutions in collaboration with Rameen Beroukhim, MD, PhD, a Dana-Farber genome biologist and co- senior author of the study. They looked for mutations caused by extra or missing copies of DNA code in the tumour genomes.
One alteration stood out: a gene called MYBL1, a transcription factor important for controlling other genes, was rearranged and missing a part of its genetic message in nearly 30 percent of the diffuse tumours categorised as grade 2 in terms of aggressiveness. The scientists went on to show that the mutated version of MYBL1 can cause tumours in mice. Previously MYLB1 was not known to cause cancer, but a closely related gene, MYB, is one of the oldest ‘proto-oncogenes’ – a normal gene that can become a cancer-causing gene.
‘The creation of these truncated genes, reminiscent in structure of the viral oncogene, is a potential driver for this type of tumour,’ said Lori Ramkissoon, PhD, co-first author along with Peleg Horowitz, MD, PhD, a neurosurgery resident, both of Dana-Farber. ‘It gives us something to follow up on and investigate the function of this gene. It may lead to a specific test for diagnosing these tumours, and we will also try to determine whether patients who have this mutation do better or worse than those lacking the mutation.’ EurekAlert

A simple, inexpensive blood test performed on trauma patients upon admission can help doctors easily identify patients at greatest risk of death, according to a new study by researchers at Intermountain Medical Center.

The Intermountain Medical Center research study of more than 9,500 patients discovered that some trauma patients are up to 58 times more likely to die than others, regardless of the severity of their original injury.

Researchers say the study findings provide important insight into the long-term prognosis of trauma patients, something not previously well understood.

‘The results were very surprising,’ said Sarah Majercik, MD, an Intermountain Medical Center surgeon and trauma researcher, whose team discovered that a tool developed at Intermountain Medical Center, called the Intermountain Risk Score, can predict mortality among trauma patients.
The Intermountain Risk Score is a computerised tool available to physicians that combines factors like age, gender, and common blood tests known as the complete blood count (CBC) and the basic metabolic profile (BMP) to determine an individual’s mortality risk.

All of the components of the tool have been helpful in evaluating individuals with medical problems like heart failure or chronic pulmonary disease. But until now, the benefit of the tool had not been tested for trauma patients hospitalised due to an accident or traumatic injury, rather than an underlying condition.

‘As surgeons, we don’t often use all of the CBC results in evaluating a patient who needs surgery for a bleeding spleen or after a motor vehicle accident, said Dr. Majercik. ‘There are certain values, such as haemoglobin, hematocrit, and platelets that we scrutinise closely as part of good clinical care, but then other parts, such as the red blood cell distribution width (RDW) that we pay no attention to at all in the acute setting. These factors are generally overlooked, even though they are part of the CBC that every trauma patient gets when he or she arrives in the emergency room.’

Data from the Intermountain Risk Score tool will allow physicians to take additional precautions with patients who are at greatest risk, and also give doctors important information to consider when talking about prognosis with patients and families.

Dr. Majercik and her colleague Benjamin Horne, PhD, director of cardiovascular and genetic epidemiology at the Intermountain Medical Center Heart Institute, reviewed the cases of 9,538 patients who had been admitted to the hospital with trauma during a six-year period.

Using the tool, the Intermountain Medical Center categorised patients according to high, moderate, and low risk levels. Some surprising findings:
High-risk men were nearly 58 times more likely to die within a year than low-risk men. Men with a moderate risk were nearly 13 times more likely to die than those with low risk.
High-risk women were 19 times more likely to die within a year than low-risk women. And women with moderate risk were five times more likely to die than those with low risk.
‘Some risk factors will be already apparent for physicians, but others aren’t intuitive,’ said Dr. Horne. For example, a trauma patient may look completely healthy apart from his or her injury. But if the Intermountain Risk Score tool uncovers an irregular red blood cell distribution width — a common sign of anaemia — that will increase his risk of dying.
‘It’s a standard part of the CBC test, but it’s not usually taken into consideration when treating a patient with injuries,’ said Dr. Horne. ‘Based on the findings of our research, it’s something that should be looked at as part of the care plan model.’
Dr. Majercik and Dr. Horne believe their research will give physicians a simple, fast way to better understand their patients’ condition, and may lead to new treatment approaches that could reduce the risk of death. Intermountain Medical Center

How do nerve cells — which can each be up to three feet long in humans — keep from rupturing or falling apart?
Axons, the long, cable-like projections on neurons, are made stronger by a unique modification of the common molecular building block of the cell skeleton. The finding, which may help guide the search for treatments for neurodegenerative diseases.
Microtubules are long, hollow cylinders that are a component of the cytoskeleton in all cells of the body. They also support transport of molecules within the cell and facilitate growth. They are made up of polymers of a building-block substance called tubulin.

‘Except for neurons, cells’ microtubules are in constant dynamic flux — being taking apart and rebuilt,’ says Scott Brady, professor and head of anatomy and cell biology at UIC and principal investigator on the study. But only neurons grow so long, he said, and once created they must endure throughout a person’s life, as much as 80 to 100 years. The microtubules of neurons are able to withstand laboratory conditions that cause other cells’ microtubules to break apart.

Brady had been able to show some time ago that the neuron’s stability depended on a modification of tubulin.

‘But when we tried to figure out what the modification was, we didn’t have the tools,’ he said.

Yuyu Song, a former graduate student in Brady’s lab and the first author of the study, took up the question. ‘It was like a detective story with many possibilities that had to be ruled out one by one,’ she said. Song, who is now a post-doctoral fellow at Howard Hughes Medical Institute at Yale School of Medicine, used a variety of methods to determine the nature of the modification and where it occurs.

She found that tubulin is modified by the chemical bonding of polyamines, positively charged molecules, at sites that might otherwise be chinks where tubulin could be broken down, causing the microtubules to fall apart. She was also able to show that the enzyme transglutaminase was responsible for adding the protective polyamines.

The blocking of a vulnerable site on tubulin would explain the extraordinary stability of neuron microtubules, said Brady. However, convincing others required the ‘thorough and elegant work’ that Song brought to it, he said. ‘It’s such a radical finding that we needed to show all the key steps along the way.’

The authors also note that increased microtubule stability correlates with decreased neuronal plasticity — and both occur in the process of ageing and in some neurodegenerative diseases. Continued research, they say, may help identify novel therapeutic approaches to prevent neurodegeneration or allow regeneration. University of Illinois at Chicago College of Medicine

A new study looking at the genomes of more than 13,000 men identified four new genetic variants associated with an increased risk of testicular cancer, the most commonly diagnosed type in young men today.
The discovery of these genetic variations—chromosomal ‘typos,’ so to speak—could ultimately help researchers better understand which men are at high risk and allow for early detection or prevention of the disease.
‘As we continue to cast a wider net, we identify additional genetic risk factors, which point to new mechanisms for disease,’ said Katherine L. Nathanson, MD, associate professor in the division of Translational Medicine and Human Genetics within the department of Medicine. ‘Certain chromosomal regions, what we call loci, are tied into testicular cancer susceptibility, and represent a promising path to stratifying patients into risk groups—for a disease we know is highly heritable.’
Tapping into three genome-wide association studies (GWAS), the researchers, including Peter A. Kanetsky, PhD, MPH, an associate professor in the department of Biostatistics and Epidemiology, analyzed 931 affected individuals and 1,975 controls and confirmed the results in an additional 3,211 men with cancer and 7,591 controls. The meta-analysis revealed that testicular germ cell tumor (TGCT) risk was significantly associated with markers at four loci—4q22, 7q22, 16q22.3, and 17q22, none of which have been identified in other cancers. Additionally, these loci pose a higher risk than the vast majority of other loci identified for some common cancers, such as breast and prostate.

This brings the number of genomic regions associated with testicular cancer up to 17—including eight new ones reported in another study.

Testicular cancer is relatively rare; however, incidence rates have doubled in the past 40 years. It is also highly heritable. If a man has a father or son with testicular cancer, he has a four-to six-fold higher risk of developing it compared to a man with no family history. That increases to an eight-to 10-fold higher risk if the man has a brother with testicular cancer.
Given this, researchers continue to investigate genetic variants and their association with cancer.
In 2009, Dr. Nathanson and colleagues uncovered variation around two genes—KITLG and SPRY4—found to be associated with an increased risk of testicular cancer. The two variants were the first striking genetic risk factors found for this disease at the time. Since then, several more variants have been discovered, but only through single GWAS studies.
‘This analysis is the first to bring several groups of data together to identify loci associated with disease,’ said Dr. Nathanson, ‘and represent the power of combining multiple GWAS to better identify genetic risk factors that failed to reach genome-wide significance in single studies.’

The team also explains how the variants associated with increased cancer risk are the same genes associated with chromosomal segregation. The variants are also found near genes important for germ cell development. These data strongly supports the notion that testicular cancer is a disorder of germ cell development and maturation. Perelman School of Medicine

Genetic medicine experts from Manchester Biomedical Research Centre at Saint Mary’s Hospital and The University of Manchester have identified a new gene responsible for causing an inherited form of tumour, known as spinal meningioma.
Meningiomas are the commonest form of tumour affecting the brain and spine. Usually meningiomas can be removed by surgery and do not recur. Occasionally people can develop more than one meningioma or many members of the same family can be affected.
A team led by Dr Miriam Smith, Professor Gareth Evans and Dr Bill Newman worked with families with a history of meningiomas affecting the spinal cord. Using a powerful new genetic sequencing technique called next generation sequencing, they were able to check all the genes of three individuals with multiple spinal meningiomas. This lead to the identification that changes in a gene called SMARCE1 lead to spinal meningiomas in some families.
In the past year 10 genes have been discovered using the new next generation sequencing technology in Manchester including genes for developmental problems, deafness, short stature and bladder problems that lead to kidney failure.
‘With our new DNA sequencing machines, we have been able to show that changes in the SMARCE1 gene are responsible for multiple spinal meningioma disease,’ said Dr Smith. ‘Before our work, doctors did not know that inherited spinal meningiomas have a completely different cause to other tumours affecting the brain and spine.
‘The next step is to develop a screening programme to assess the risk of developing spinal tumours for individuals in affected families, and to investigate possible treatments to prevent the spinal tumours from growing.’
Professor Richard Marias, Director of Cancer Research UK’s Paterson Institute at The University of Manchester, said ‘This research highlights the complexity of tumour diagnosis. Such detailed molecular characterisation underpins current thoughts about how meningioma and cancer will be managed in the future and is at the heart of the personalised medicine approach.’
Just over two people in every 100,000 develop meningiomas in the head and spine, with twice as many women as men diagnosed with the condition. The University of Manchester