Research led by St. Jude Children’s Research Hospital scientists has identified a possible lead in treatment of two childhood leukaemia subtypes known for their dramatic loss of chromosomes and poor treatment outcomes.
The findings also provide the first evidence of the genetic basis for this high-risk leukaemia, which is known as hypodiploid acute lymphoblastic leukaemia (ALL). Normal human cells have 46 chromosomes, half from each parent, but hypodiploid ALL is characterised by fewer than 44 chromosomes. Chromosomes are highly condensed pieces of DNA, the molecule that carries the inherited instructions for assembling and sustaining a person.
The study, the largest ever focused on hypodiploid ALL, confirmed that this tumour has distinct subtypes distinguished by the number of chromosomes lost and the submicroscopic genetic alterations they harbour. Researchers found evidence suggesting more than one-third of patients with a subtype known as low hypodiploid ALL have Li-Fraumeni syndrome. Families with Li-Fraumeni syndrome harbour inherited mutations in the TP53 tumour suppressor gene and have a high risk of a range of cancers. Hypodiploid ALL had not previously been recognised as a common manifestation of Li-Fraumeni syndrome.
Researchers reported that the major hypodiploid subtypes are both sensitive to a family of compounds that block the proliferation of cancer cells. The compounds include drugs already used to treat other cancers. The subtypes are low hypodiploid ALL, characterised by 32 to 39 chromosomes, and near haploid ALL, which has 24 to 31 chromosomes.
‘This study is a good example of the important insights that can be gained by studying the largest possible number of patients in as much detail as possible. This approach led us to key insights about these leukaemia subtypes that we would otherwise have missed,’ said the study’s senior and corresponding author, Charles Mullighan, MBBS(Hons), MSc, M.D., an associate member of the St. Jude Pathology Department. Mullighan is a Pew Scholar in Biomedical Sciences.
The near haploid and low hypodiploid ALL subtypes represent 1 to 2 percent of the estimated 3,000 pediatric ALL cases diagnosed annually in the U.S. But they account for a much larger number of ALL treatment failures. Today more than 90 percent of young ALL patients will become long-term survivors, compared to 40 percent for patients with these two high-risk subtypes. St. Jude researchers led the study in collaboration with investigators from the Children’s Oncology Group, the world’s largest organisation devoted exclusively to childhood and adolescent cancer research.
‘The cure rate for hypodiploid ALL is only about half that obtained overall for children with ALL. The findings of this study are very important and have the potential to impact how this high-risk subset of childhood ALL is treated,’ said Stephen Hunger, M.D., chair of the Children’s Oncology Group ALL committee and one of the paper’s co-authors. ‘This study grew out of the efforts of Hank Schueler, a teenager who died from hypodiploid ALL. He wanted to find ways to help treat other children with this type of leukaemia. After he passed away, his parents established a foundation to support research in hypodiploid ALL. We thought that one way to do this was to conduct the genomic analyses reported in this paper. These findings would not have been possible without Hank’s idea and without support from the Schueler family.’
Researchers used a variety of laboratory techniques to look for genetic abnormalities in cancer cells from 124 pediatric patients missing at least one chromosome. The patients included 68 with near haploid ALL and 34 with low hypodiploid ALL. Investigators also checked white blood cells collected when 89 of the 124 patients were in remission. The study included whole-genome sequencing of the entire cancer and normal genomes of 20 patients with near haploid or low hypodiploid subtypes. For another 20 patients, investigators deciphered just DNA involved in protein production. Researchers also screened cancer cells from 117 adult ALL patients, including 11 with the low hypodiploid subtype.
The whole genome sequencing was done in conjunction with the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project. The project has sequenced the complete normal and cancer genomes of more than 600 children and adolescents with some of the most aggressive and least understood cancers.
Near haploid ALL was characterised by alterations in six genes and increased activity in key pathways that help regulate cell division and development. Disruption of these pathways, known as Ras and PI3K, has been linked to other cancers. The changes were found in 71 percent of near haploid ALL patients and included deletion of the NF1 gene. The gene had not previously been linked to high-risk leukemia. Other alterations involved the genes NRAS, KRAS, MAPK1, FLT3 and PTPN11.
Low hypodiploid ALL in both adults and children was linked to mutations in the TP53 tumour suppressor gene. The gene was altered in 91 percent of pediatric patients with the ALL subtype and in 10 of the 11 adults with low hypodiploid ALL included in the study. Other common alterations involved RB1, another tumour suppressor gene.
About 38 percent of children with low hypodiploid ALL also carried TP53 abnormalities in non-cancerous blood cells. The mutations included many previously linked to Li-Fraumeni syndrome, which is characterized by changes in TP53.
Further evidence linking low hypodiploid ALL to Li-Fraumeni syndrome came when researchers found the same TP53 mutation in two generations of the same family. The father was 31 years old when he was found to have a brain tumour associated with Li-Fraumeni syndrome. His son later developed low hypodiploid ALL.
‘Identification of children with low-hypodiploid ALL and inherited TP53 mutations could help expand the use of life-saving cancer screening,’ said Linda Holmfeldt, Ph.D., a St. Jude postdoctoral fellow. She and Lei Wei, Ph.D., of the St. Jude Department of Computational Biology and formerly of Pathology, are the study’s co-first authors. ‘Screening helps save lives by finding cancers much earlier when the odds of a cure are greatest,’ Holmfeldt said. St. Jude Children’s Research Hospital

Men who develop prostate cancer after inheriting a faulty gene need immediate surgery or radiotherapy rather than being placed under surveillance, as their disease is more aggressive than other types, a new study has found.
A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust found prostate cancers spread more quickly and were more often fatal in men who had inherited a faulty BRCA2 gene than in men without the faulty gene.
The research, funded by the Ronald and Rita McAulay Foundation and Cancer Research UK, could challenge current NHS guidelines for prostate cancer, under which BRCA2 mutation carriers are offered the same treatment options as non-carriers.
It is often difficult to tell at diagnosis whether prostate cancer will be life-threatening or not, and while treatment options for early-stage disease include surgery and radiotherapy, many men instead receive active surveillance to see if the disease starts to progress.
The new study is the largest to compare prostate cancer patients with and without BRCA mutations, in order to tell whether gene testing should help to direct management options.
Senior author Professor Ros Eeles, Professor of Oncogenetics at The Institute of Cancer Research (ICR) and Honorary Consultant in Clinical Oncology at The Royal Marsden, said: ‘It is clear from our study that prostate cancers linked to inheritance of the BRCA2 cancer gene are more deadly than other types. It must make sense to start offering affected men immediate surgery or radiotherapy, even for early-stage cases that would otherwise be classified as low-risk. We won’t be able to tell for certain that earlier treatment can benefit men with inherited cancer genes until we’ve tested it in a clinical trial, but the hope is that our study will ultimately save lives by directing treatment at those who most need it.’
The team from the ICR and The Royal Marsden, with collaborators across the UK, examined the medical records of 61 BRCA2-mutation carriers, 18 BRCA1-mutation carriers and 1,940 non-carriers.
They found BRCA1/2 mutation carriers were more likely to be diagnosed with advanced stage prostate cancers (37 per cent versus 28 per cent) or cancer that had already spread (18 per cent versus nine per cent) than non-carriers. Among those whose cancers had not spread out of the prostate at diagnosis, within five years more carriers than non-carriers had metastatic disease (23 per cent versus seven per cent).
Patients with BRCA2-mutations were also significantly less likely to survive the cancer, living an average of 6.5 years compared with 12.9 years for non-carriers. The team concluded that a BRCA2 test could be used in combination with other factors as a prognostic test. Men with a BRCA1 mutation also had a shorter average survival time of 10.5 years, but there was not a statistically significant difference with non-carriers. ICR

In the summer of 1968, a new strain of influenza appeared in Hong Kong. This strain, known as H3N2, spread around the globe and eventually killed an estimated 1 million people.
A new study from MIT reveals that there are many strains of H3N2 circulating in birds and pigs that are genetically similar to the 1968 strain and have the potential to generate a pandemic if they leap to humans. The researchers, led by Ram Sasisekharan, the Alfred H. Caspary Professor of Biological Engineering at MIT, also found that current flu vaccines might not offer protection against these strains.
‘There are indeed examples of H3N2 that we need to be concerned about,’ says Sasisekharan, who is also a member of MIT’s Koch Institute for Integrative Cancer Research. ‘From a pandemic-preparedness point of view, we should potentially start including some of these H3 strains as part of influenza vaccines.’
The study also offers the World Health Organization and public-health agencies’ insight into viral strains that should raise red flags if detected.
In the past 100 years, influenza viruses that emerged from pigs or birds have caused several notable flu pandemics. When one of these avian or swine viruses gains the ability to infect humans, it can often evade the immune system, which is primed to recognise only strains that commonly infect humans.
Strains of H3N2 have been circulating in humans since the 1968 pandemic, but they have evolved to a less dangerous form that produces a nasty seasonal flu. However, H3N2 strains are also circulating in pigs and birds.
Sasisekharan and his colleagues wanted to determine the risk of H3N2 strains re-emerging in humans, whose immune systems would no longer recognise the more dangerous forms of H3N2. This type of event has a recent precedent: In 2009, a strain of H1N1 emerged that was very similar to the virus that caused a 1918 pandemic that killed 50 million to 100 million people.
‘We asked if that could happen with H3,’ Sasisekharan says. ‘You would think it’s more readily possible with H3 because we observe that there seems to be a lot more mixing of H3 between humans and swine.’
In the new study, the researchers compared the 1968 H3N2 strain and about 1,100 H3 strains now circulating in pigs and birds, focusing on the gene that codes for the viral haemagglutinin (HA) protein.
After comparing HA genetic sequences in five key locations that control the viruses’ interactions with infected hosts, the researchers calculated an ‘antigenic index’ for each strain. This value indicates the percentage of these genetic regions identical to those of the 1968 pandemic strain and helps determine how well an influenza virus can evade a host’s immune response.
The researchers also took into account the patterns of attachment of the HA protein to sugar molecules called glycans. The virus’ ability to attach to glycan receptors found on human respiratory-tract cells is key to infecting humans.
Seeking viruses with an antigenic index of at least 49 percent and glycan-attachment patterns identical to those of the 1968 virus, the research team identified 581 H3 viruses isolated since 2000 that could potentially cause a pandemic. Of these, 549 came from birds and 32 from pigs.
The researchers then exposed some of these strains to antibodies provoked by the current H3 seasonal-flu vaccines. As they predicted, these antibodies were unable to recognise or attack these H3 strains. Of the 581 HA sequences, six swine strains already contain the standard HA mutations necessary for human adaptation, and are thus capable of entering the human population either directly or via genetic reassortment, Sasisekharan says.
‘One of the amazing things about the influenza virus is its ability to grab genes from different pools,’ he says. ‘There could be viral genes that mix among pigs, or between birds and pigs.’
Sasisekharan and colleagues are now doing a similar genetic study of H5 influenza strains. The H3 study was funded by the National Institutes of Health and the National Science Foundation. MIT

Scientists at The University of Manchester have made important advances in understanding why our immune system can attack our own tissues resulting in eye and kidney diseases. It is hoped the research will pave the way for the development of new treatments for the eye condition age-related macular degeneration (AMD) and the kidney condition atypical Haemolytic Uremic Syndrome (aHUS).
Both AMD, which affects around 50 million people worldwide, and aHUS, a rare kidney disease that affects children, are associated with incorrectly controlled immune systems. A protein called complement factor H (CFH) is responsible for regulating part of our immune system called the complement cascade. Genetic alterations in CFH have been shown to increase a person’s risk of developing either AMD or aHUS, but rarely both. Why this is the case has never been explained until now.
Researchers from the Wellcome Trust Centre for Cell Matrix Research and the Ophthalmology and Vision Research Group in The University of Manchester’s Institute of Human Development have been expanding on their previous work that demonstrated a single common genetic alteration in CFH prevents it from fully protecting the back of the human eye. The research teams of Professor Tony Day and Professor Paul Bishop found that a common genetically altered form of CFH associated with AMD couldn’t bind properly to a layer under the retina called Bruch’s membrane. Having a reduced amount of CFH in this part of the eye leads to low-level inflammation and tissue damage, eventually resulting in AMD.
However, this mutation that changes CFH function in the eye has no affect on the protein’s ability to regulate the immune system in the kidney. A cluster of genetic mutations in a completely different part of CFH are associated with the kidney disease aHUS, but these have no affect on the eyes.
In their most recent study, which was funded by the Medical Research, the Manchester researchers have identified why these mutations in CFH result in diseases in very specific tissues. Professor Day explains: ‘For the first time we’ve been able to identify why these protein mutations are so tissue specific. We’re hoping our discovery will open the door to the development of tissue specific treatments to help the millions of people diagnosed with AMD every year.’
The research team looked at the two parts of CFH affected by the mutations. Both regions are capable of recognising host tissues, through interacting with sugars called glycosaminoglycans (GAGs). Successfully recognising these GAGs lets CFH build up a protective layer on the surface of our tissues that prevents our own immune system from attacking them.
It had always been believed that the region with mutations associated with aHUS was the most important for host recognition and for years people have been researching how to readdress immune dysregulation based on this belief. However, the recent discovery of a single common genetic alteration in the other part of CFH that is associated with eye disease raised the possibility that this previous opinion was not fully accurate. The University of Manchester