Continuing a series of groundbreaking discoveries begun in 2010 about the genetic causes of the third most common form of inherited muscular dystrophy, an international team of researchers led by a scientist at Fred Hutchinson Cancer Research Center has identified the genes and proteins that damage muscle cells, as well as the mechanisms that can cause the disease.
The discovery could lead to a biomarker-based test for diagnosing facioscapulohumeral muscular dystrophy (FSHD), and the findings have implications for developing future treatments as well as for cancer immunotherapies in general.
The work establishes a viable roadmap for how the expression of the DUX4 gene can cause FSHD. Whether this is the sole cause of FSHD is not known; however, the latest findings ‘are about as strong of evidence as you can get’ of the genetic link, said corresponding author Stephen Tapscott, M.D., Ph.D., a member of the Hutchinson Center’s Human Biology Division.
Tapscott and colleagues sought answers to the questions about what the DUX4 protein does both normally in the body and in the FSHD disease process. In the latest study, they identified that the DUX4 protein regulates many genes that are normally expressed in the male germ line but are abnormally expressed in FSHD muscle. Germ line cells are inherited from parents and passed down to their offspring.
‘This study is a significant step forward by solidifying that the DUX4 transcription factor causes this disease, while offering a number of viable mechanisms for why the muscle is damaged,’ Tapscott said. Transcription factors are tools that cells use to control gene expression. Genes that are ‘turned on’ in the body are ‘transcribed,’ or translated, into proteins.
Now that scientists know that targets for DUX4 are expressed in skeletal muscle, an antibody- or RNA-based test could be developed to diagnose FSHD by examining muscle tissue from a biopsy, Tapscott said. Such biomarker-based tests also could be used to determine how well new treatments are working to suppress FSHD.
The study also discovered that DUX4 regulates cancer/testis antigens. Cancer/testis antigens are encoded by genes that are normally expressed only in the human germ line, but are also abnormally expressed in various tumour types, including melanoma and carcinomas of the bladder, lung and liver.
‘This knowledge now gives us a way to manipulate the expression of cancer/ testis antigens, potentially opening the opportunity to use these antigens in a cancer vaccine,’ Tapscott said. Fred Hutchinson Cancer Research Center

Tilting the scales in an ongoing debate, University of Wisconsin-Madison researchers have found new evidence that human cytomegalovirus (HCMV) is associated with glioblastoma multiforme (GBM), the brain cancer that killed Sen. Edward Kennedy.
The findings confirm what only a handful of scientists have found, but in a manner that University of Wisconsin School of Medicine and Public Health researchers believe enhances the scientific rigor of earlier studies.
The study hints for the first time that HCMV may work differently than other cancer-related viruses – possibly by affecting only tumour stem cells, self-renewing cells that keep the tumour growing. The new research may place HCMV in an expanding group of viruses associated with cancer.
‘As many as 15 to 20 percent of all human cancers are caused by viruses, and the number is growing,’ says HCMV expert Dr. Robert Kalejta, associate professor of oncology at the UW School of Medicine and Public Health (SMPH). ‘The viruses may not cause cancer on their own, but they play a critical role in the process.’
Among others, human papilloma virus (HPV) causes cervical cancer, Epstein-Barr virus (EBV) causes lymphoma and hepatitis C virus (HCV) causes liver cancer.
HCMV’s role in GBM has been debated, with many scientists and clinicians remaining skeptical. Oncologist Dr. Charles Cobbs of California Pacific Medical Center has been the main proponent of the theory that HCMV contributes to GBM.
Dr. John Kuo, assistant professor of neurological surgery and human oncology and a cancer stem cell scientist at the School of Medicine and Public Health, was one of the skeptical ones, but he says he’s now convinced that HCMV is associated with human GBM specimens.
Still, the association does not prove a causal relationship between HCMV and the development of GBM, he says.
‘This study may open up a new unexplored area of research for this incurable disease,’ says Kuo, who is director of the Comprehensive Brain Tumor Program at UW Hospital and Clinics. He also co-ordinates clinical trials as chair of the brain tumour group at the Carbone Cancer Center.
Two years ago, Kalejta’s team added support to Cobb’s position when it showed that two HCMV proteins shut down a key protein that restricts tumour growth in general.
‘HCMV can also do every one of the things that are generally considered the 10 hallmarks of cancer,’ says Kalejta, a member of the McArdle Laboratory for Cancer Research, Carbone Cancer Center, Stem Cell and Regenerative Medicine Center and Institute for Molecular Virology at UW-Madison.
The problem with studying HCMV is that the virus is present in a harmless way in almost everyone, so scientists can’t ask if HCMV-positive people are more likely to get cancer than people without HCMV.
Kalejta’s postdoctoral fellow Dr. Padhma Ranganatan used a standard laboratory test, rather than the ultra-sensitive test Cobb has used, to see if HCMV was present in 75 GBM samples. The UW-Madison researchers also looked to see if the entire virus genome – all of its DNA – rather than just a portion of it was present in the tissues. Finally, they wanted to learn if all cells within the tumour or just some of them were infected.
The analysis showed that HCMV is statistically more likely to be present in GBM sample tissues than in other brain tumour and epileptic brain tissues. The whole virus genome, not a portion of it, was present in GBM samples. And the data suggested that a minority of GBM cells were infected with HCMV.
‘We hypothesize that HCMV may be infecting only tumour stem cells, unlike other viruses, which infect every single tumour cell,’ says Kalejta. ‘This leads us to predict that HCMV functions by a unique mechanism that no other virus uses.’ University of Wisconsin-Madison

The discovery of a gene that causes a form of hereditary spastic paraplegia may provide scientists with an important insight into what causes axons, the stems of our nerve cells, to degenerate in conditions such as multiple sclerosis.An international team of scientists led by Dr Evan Reid at the University of Cambridge and Dr Stephan Zuchner from the University of Miami reports that mutations in the gene known as reticulon 2 on chromosome 19 cause a form of hereditary spastic paraplegia (HSP). HSP is characterised by progressive stiffness and contraction (spasticity) of the legs, caused by selective and specific degeneration of axons.
The team identified three mutations in the reticulon 2 gene as causing a type of HSP – in one case, this mutation included an entire deletion of the gene. In addition, the researchers showed that reticulon 2 interacts with another gene, spastin. Mutations in this gene cause the most common form of hereditary spastic paraplegia.
Reticulon 2 provides the genetic code for a reticulon protein that is a member of a family of proteins recently shown to have a key role in shaping the endoplasmic reticulum. The endoplasmic reticulum is a network of interconnected sheets and tubules that extends throughout the cytoplasm in nearly all cells.
The endoplasmic reticulum has several functions, including protein synthesis, calcium signalling and the regulation of other components of the cell. Recent data suggest the sheets are involved in protein synthesis, whereas the tubules are specialised to carry out the other functions.
This new study provides the most direct evidence to date that defects in how the endoplasmic reticulum is shaped and formed could underlie axon degeneration. When axons degenerate, signals are unable to pass through the nerve cells, leading to a breakdown of communication within the central nervous system. This is common in degenerative diseases of the nervous system, such as multiple sclerosis.
‘Our work highlights important new disease mechanisms, which may provide a platform for us to study how axons are damaged in devastating illnesses such as HSP, and perhaps even in multiple sclerosis, which in some cases is very similar to HSP,’ explains Dr Reid, a Wellcome Trust Senior Research Fellow in Clinical Science. ‘But we must not forget how this work may immediately directly benefit families affected by HSP, for whom the discovery now opens up the possibility of genetic counselling and testing.’ Wellcome Trust

A recent analysis of clinical trial results performed by the Radiation Therapy Oncology Group (RTOG) demonstrate that a chromosomal abnormality—specifically, the absence (co-deletion) of chromosomes 1p and 19q—have definitive prognostic and predictive value for managing the treatment of adult patients with pure and mixed anaplastic oligodendrogliomas. The presence of the chromosomal abnormality was associated with a substantially better prognosis and near-doubling of median survival time when treatment with combined chemotherapy and radiation therapy was compared to treatment with radiation therapy alone.
Oligodendrogliomas are uncommon tumours that represent approximately 4.0% of all brain tumours. Mixed oliogdendrogliomas (those also containing astrocytic elements) account for 1.0% of all brain tumours. Pure and mixed oligodendrogliomas that contain anaplastic (malignant) cells typically grow more rapidly than non-anaplastic tumours.

The RTOG 9402 trial A Phase III Intergroup Randomized Comparison of Radiation Alone vs. Pre-Radiation Chemotherapy for Pure and Mixed Anaplastic Oligodendrogliomas was conducted with four other National Cancer Institute (NCI)-supported co-operative groups. Trial participants had a pathologically confirmed pure or mixed anaplastic oligodendroglioma and were randomly assigned into one of two treatment arms. The 148 participants randomised to Arm 1 were treated with PCV (procarbazine, CCNU [lomustine] and vincristine) chemotherapy and radiation therapy (RT), and the 143 participants randomised to Arm 2 were treated with RT alone.

RTOG 9402 study results showed no survival benefit for patients treated with early PVC chemotherapy plus RT over RT alone. Although a significant impact on median progression-free survival time was realised (2.6 years versus 1.7 years for RT alone), the regimen was associated with significantly more adverse side effects. The study authors also reported that study participants in both arms whose tumour lacked chromosomes 1p and 19q had longer median survival times as compared with participants without these deletions (> 7 vs. 2.8 years, respectively). This led the study authors to conclude that ‘tumours with 1p and 19q co-deletion are less aggressive or more responsive to PCV chemotherapy or both.’

A recent analysis undertaken of the RTOG 9402 data (at a median study participant follow-up time of 11 years) is planned for submission to the 2012 American Society of Clinical Oncology Annual Meeting. However, due to the finding’s significance for patient care, results are reported here in advance of submission. Radiation Therapy Oncology Group

New research from Queen Mary, University of London has uncovered a gene which plays a key role in the development of oesophageal cancer (cancer of the gullet).
The researchers studied families who suffer a rare inherited condition making them highly susceptible to the disease and found that a fault in a single gene was responsible. Initial studies suggest that the gene could play a role in the more common, non-inherited form of the disease, revealing a new target for treating this aggressive type of cancer.
Oesophageal cancer affects more than 8,000 people each year in the UK and rates are rising. It is more common in the UK than anywhere else in Europe.
Survival rates are poor compared to other types of cancer with only eight per cent of people alive five years after diagnosis. Scientists know little about how oesophageal cancer develops and very few drugs for targeting the disease are currently available.
The new study was led by Professor David Kelsell from Barts and the London Medical School, Queen Mary, University of London with collaborators from the University of Dundee and the University of Liverpool.
The research concentrated on three families with a hereditary condition called tylosis with oesophageal cancer. This condition affects the skin and mouth and sufferers have a 95 per cent chance of developing oesophageal cancer by the age of 65.
The research revealed that all three families carried a faulty version of a gene called RHBDF2.
Experiments showed that this gene plays an important role in how cells that line the oesophagus, and cells in the skin, respond to injury. When the gene is functioning normally it ensures that cells grow and divide in a controlled fashion to help heal a wound.
However, in tylosis patients’ cells, and in cells from oesophageal cancers, the gene malfunctions. This allows cells to divide and grow uncontrollably, causing cancer.
Professor Kelsell explains: ‘In studying this relatively rare condition, we have made an important discovery about a cancer that is all too common. Finding a genetic cause for this aggressive cancer, and understanding what that gene is doing, is an enormous step forward.
‘By analysing the complex biology which causes a particular type of cancer we begin to understand which treatments might be effective and also which treatments are unlikely to help.’ Queen Mary University of London