Scientists at A*STAR’s Institute of Medical Biology (IMB) and the Bioinformatics Institute (BII) have found new clues to early detection and personalised treatment of ovarian cancer, currently one of the most difficult cancers to diagnose early due to the lack of symptoms that are unique to the illness.

There are three predominant cancers that affect women – breast, ovarian and womb cancer. Of the three, ovarian cancer is of the greatest concern as it is usually diagnosed only at an advanced stage due to the absence of clear early warning symptoms. Successful treatment is difficult at this late stage, resulting in high mortality rates. Ovarian cancer has increased in prevalence in Singapore as well as other developed countries recently. It is now the fifth most common cancer in Singapore amongst women, with about 280 cases diagnosed annually and 90 deaths per year.

IMB scientists have successfully identified a biomarker of ovarian stem cells, which may allow for earlier detection of ovarian cancer and thus allow treatment at an early stage of the illness.

The team has identified a molecule, known as Lgr5, on a subset of cells in the ovarian surface epithelium. Lgr5 has been previously used to identify stem cells in other tissues including the intestine and stomach, but this is the first time that scientists have successfully located this important biomarker in the ovary. In doing so, they have unearthed a new population of epithelial stem cells in the ovary which produce Lgr5 and control the development of the ovary. Using Lgr5 as a biomarker of ovarian stem cells, ovarian cancer can potentially be detected earlier, allowing for more effective treatment at an early stage of the illness (see Annex A).

Of the different types of ovarian cancers detected, high-grade serous ovarian carcinoma (HG-SOC) is the most prevalent of epithelial ovarian cancers. It has also proven to be one of the most lethal ovarian cancers, with only 30 per cent of such patients surviving more than five years after diagnosis. HG-SOC remains poorly understood, with a lack of biomarkers identified for clinical use, from diagnosis to prognosis of patient survival rates.

By applying bioinformatics analysis on big cancer genomics data, BII scientists were able to identify genes whose mutation status could be used for prognosis and development of personalized treatment for HG-SOC.

The gene, Checkpoint Kinase 2 (CHEK2), has been identified as an effective prognostic marker of patient survival. HG-SOC patients with mutations in this gene succumbed to the disease within five years of diagnosis, possibly because CHEK2 mutations were associated with poor response to existing cancer therapies.

Mortality after diagnosis currently remains high, as patients receive similar treatment options of chemotherapy and radiotherapy despite the diverse nature of tumour cells within tumours and across different tumour samples. With these findings, personalised medicine for ovarian cancer could be developed, with targeted treatment that would be optimised for subgroups of patients. A*Star

Stomach cancers fall into four distinct molecular subtypes researchers with The Cancer Genome Atlas (TCGA) Network have found. In the study, the scientists report that this discovery could change how researchers think about developing treatments for stomach cancer, also called gastric cancers or gastric adenocarcinomas.

Instead of considering gastric cancer as a single disease, as has been done in the past, researchers will now be able to explore therapies in defined sets of patients whose tumours have specific genomic abnormalities. Stomach cancers are a leading cause of cancer-related mortality worldwide, resulting in an estimated 723,000 deaths annually.

Previous attempts to examine the clinical characteristics of gastric cancer were hindered by how differently cancer cells can look under a microscope, even when from the same tumour. The researchers hope that the new classification system will serve as a valuable adjunct to the current pathology classification system, which has two categories: diffuse and intestinal.

“A key advance with this project is that we have identified and developed a much more useful classification system to find groups of gastric cancer that have distinct molecular features, and at the same time, we also identified key targets to pursue in different groups of patients,” said Adam Bass, M.D., Harvard Medical School, Dana-Farber Cancer Institute, the Broad Institute, Boston, and one of the lead investigators on the project. “This will provide a strong foundation for categorizing the disease and for doing so in a way in which we can develop clinical trials based on some of the critical molecular alterations that are driving different classes of cancers.”

The researchers identified the new subgroups through complex statistical analyses of molecular data from 295 tumours. They used six molecular analysis platforms including DNA sequencing, RNA sequencing, and protein arrays.

Tumours in the first group, which represented 9 percent of the tumours, were positive for Epstein-Barr virus (EBV) and had several other molecular commonalities. Tumours in a second subgroup (22 percent of the tumours) had high microsatellite instability (MSI), which is the tendency for mutations to accumulate in repeated sequences of DNA. The remaining subgroups differed in the level of somatic copy number alterations (SCNAs), which can result from duplication or deletion of sections of the genome. The tumours in the third subgroup, which comprised 20 percent of the tumours, were considered to have a low level of SCNAs and were called genomically stable. The remaining 50 percent of tumours were classified as chromosomally unstable, with a high level of SCNAs.

The EBV-positive subgroup of tumours was of particular interest. EBV is best known in the United States as the cause of infectious mononucleosis, which is characterized by fever, sore throat, and swollen lymph glands, especially in the neck. EBV is also suspected of causing certain cancers, including nasopharyngeal carcinoma and some types of lymphoma. Previous research had shown that EBV can be detected in a minority of gastric adenocarcinomas and that EBV genes are expressed in those tumours. However, this study found that the presence of EBV in gastric tumours is associated with a number of other molecular characteristics.

First, the researchers observed that EBV-positive tumours displayed a high frequency of mutations in the PIK3CA gene, which codes for a component of a protein, PI3-kinase, which is essential for cell growth and division and many other cellular activities that are important in cancer. Although 80 percent of EBV-positive tumours harboured a protein-changing alteration in PIK3CA, PIK3CA mutations were found in 3 percent to 42 percent of tumours of the other gastric cancer subtypes. The scientists suggested that EBV-positive tumours might respond to PI3-kinase inhibitors, some of which are in the early stages of testing in clinical trials but are not yet approved by the U.S. Food and Drug Administration for general use.

Some tumours in the EBV-positive subgroup also showed more gene copies being produced in a chromosomal region that contains the JAK2 gene. The JAK2 protein facilitates cell growth and division, and the increased expression of JAK2 may inappropriately activate cell growth. The amplified region also contains the genes for two proteins, PD-L1 and PD-L2, which suppress immune responses; their increased expression may help tumours escape destruction by the immune system. The investigators suggested that these findings support the evaluation of JAK2 inhibitors and PD-L1/2 antagonists for the treatment of EBV-positive gastric cancers.

And the EBV-positive subgroup showed a far higher prevalence of DNA hypermethylation than any other cancer subtype reported by TCGA researchers. Methylation is the process of adding methyl groups to DNA, which reduces gene expression. Hypermethylation occurs when this mechanism continues aberrantly, quieting genes that should be active. In the EBV-positive tumour subgroup, hypermethylation was most often observed in the promoter regions of genes, which would prevent the expression of the genes.
‘Gaining these insights into the connection between EBV and gastric cancer is the type of groundbreaking research that NIH is pleased to be a part of. We look forward to the potential clinical implications of this discovery,’ said NIH Director Francis S. Collins, M.D., Ph.D. The Cancer Genome Atlas

Scientists at the Salk Institute for Biological Studies have identified a gene that regulates sleep and wake rhythms.

The discovery of the role of this gene, called Lhx1, provides scientists with a potential therapeutic target to help night-shift workers or jet lagged travellers adjust to time differences more quickly. The results can point to treatment strategies for sleep problems caused by a variety of disorders.

“It’s possible that the severity of many dementias comes from sleep disturbances,” says Satchidananda Panda, a Salk associate professor who led the research team. “If we can restore normal sleep, we can address half of the problem.”

Every cell in the body has a “clock” – an abundance of proteins that dip or rise rhythmically over approximately 24 hours. The master clock responsible for establishing these cyclic circadian rhythms and keeping all the body’s cells in sync is the suprachiasmatic nucleus (SCN), a small, densely packed region of about 20,000 neurons housed in the brain’s hypothalamus.

More so than in other areas of the brain, the SCN’s neurons are in close and constant communication with one another. This close interaction, combined with exposure to light and darkness through vision circuits, keeps this master clock in sync and allows people to stay on essentially the same schedule every day. The tight coupling of these cells also helps make them collectively resistant to change. Exposure to light resets less than half of the SCN cells, resulting in long periods of jet lag.

In the new study, researchers disrupted the light-dark cycles in mice and compared changes in the expression of thousands of genes in the SCN with other mouse tissues. They identified 213 gene expression changes that were unique to the SCN and narrowed in on 13 of these that coded for molecules that turn on and off other genes. Of those, only one was suppressed in response to light: Lhx1.

“No one had ever imagined that Lhx1 might be so intricately involved in SCN function,” says Shubhroz Gill, a postdoctoral researcher and co-first author of the paper. Lhx1 is known for its role in neural development: it’s so important, that mice without the gene do not survive. But this is the first time it has been identified as a master regulator of light-dark cycle genes.

By recording electrical activity in the SCN of animals with reduced amounts of the Lhx1 protein, the researchers saw that the SCN neurons weren’t in sync with one another, despite appearing rhythmic individually.

“It was all about communication–the neurons were not talking to each other without this molecule,” says Ludovic Mure, a postdoctoral researcher and an author on the paper. A next step in the work will be to understand exactly how Lhx1 affects the expression of genes that creates this synchronicity.

Studying a mouse version of jet lag–an 8-hour shift in their day-night cycle–the scientists found that those with little or no Lhx1 readjusted much faster to the shift than normal mice. This suggests that because these neurons are less in sync with one another, they are more easily able to shift to a new schedule, though it is difficult for them to maintain that schedule, Panda says.

These mice also exhibited reduced activity of certain genes, including one that creates vasoactive intestinal peptide or Vip, a molecule that has important roles in development and as a hormone in the intestine and blood. In the brain, Vip affects cell communication, but nobody had known that Lhx1 regulated it until now, Panda says. Interestingly, the team also found that adding Vip restored cell synchrony in the SCN.

“This approach helped us to close that knowledge gap and show that Vip is a very important protein, at least for SCN,” Panda says. “It can compensate for the loss of Lhx1.”

On the other hand, cutting back on Vip could be another way to treat jet lag. Vip could be an even easier drug target compared with Lhx1 because Vip is secreted from cells rather than inside cells, Panda says. “If we find a drug that will block the Vip receptor or somehow break down Vip, then maybe that will help us reset the clock much faster,” he adds. Salk Institute for Biological Studies

Babies suffering from bacterial infections like sepsis could benefit from better treatment, thanks to a ground-breaking study.

For the first time Edinburgh researchers have been able to detect and decode a signal generated from a baby’s DNA that can tell doctors whether or not a bacterial infection is present in the bloodstream.  The findings could help develop a test for bacterial infection in newborns, using a single drop of blood.

Immediate detection of such infections, which are a major cause of death among young children, is currently impossible as no simple test exists.

The Edinburgh team identified a signal consisting of 52 molecular characters – like a biological tweet – that is specific to bacterial infection.

The researchers have spent the past decade trying to unravel the complexities of blood poisoning and its treatment among premature and full-term babies.

They say that the genome’s signal provides critical, immediate information on the infection.

Using blood samples from newborn babies in Edinburgh, the study investigated thousands of signals written in biological code known as messenger RNAs.  Through meticulous code-breaking the scientists were able to decipher with close to 100 per cent accuracy the signals generated by an infant’s genome that specifically tell if they are suffering from sepsis.

Diagnosing sepsis in newborns is extremely difficult, as signs of infection, such as a high temperature, may not occur – or if they do, they may not be due to an infection.  Currently the most reliable way to detect infection is by detecting the bacteria in the blood but require a large volume of blood.

Just as a Twitter user can send a 140 character message so a baby’s genome produces short messages or signals that produce code information to communicate with the infant’s immune and metabolic systems so that it can fight the infection. The 52-character ‘tweet’ or message that we have identified appears to be specific for bacterial but not viral infection. This type of signal could also be used to detect infection in children and adults. We are now working on ways of using a single drop of blood to detect this vital signal. This work is also leading us onto a response to tackling antibiotics resistance. University of Edinburgh

Scientists at the Max Planck Institute for Biology of Ageing in Cologne and University College London have now unearthed the way in which a specific genetic mutation leads to neuronal damage in two serious afflictions. In rare cases, patients may even suffer from these two diseases, amyotrophic lateral sclerosis and frontotemporal dementia, at the same time.

Amyotrophic lateral sclerosis is a devastating type of motor neuron disease that causes rapid weakening of muscles and death. Frontotemporal dementia is the second most common cause of dementia in people under 65. It causes distressing symptoms, including changes in personality and behaviour and problems with language and thinking.  The DNA of affected patients contains a mutation of the gene C9orf72: There are thousands of repeats of a specific short segment of genetic material, whereas in unaffected persons, there are only up to thirty copies of this segment. This specific genetic alteration is the cause of illness in around eight percent of patients with this type of motor neuron disease or dementia. Eight percent is a relatively high proportion. For instance, less than one percent of the causes in Alzheimer’s disease are genetic.

Researchers at the Max Planck Institute for Biology of Ageing, the Institute of Neurology and Institute for Healthy Ageing at University College London have now discovered that the repeats in the mutant gene cause neurodegeneration by making toxic proteins.
Fruitflies can undergo neurodegeneration in a similar way to humans

Previously it was thought that the problem could be a consequence of disruption of the gene by the inserted repeats. Another theory was that the repeats produce a different type of toxic RNA molecule. It now turns out that the repeats in the mutant gene can produce a variety of proteins and that two of these are extremely toxic to nerve cells. Both are highly enriched in arginine, an amino acid.

To pinpoint the role of the toxic proteins, the researchers produced artificial repeat segments that could produce potentially toxic RNA and protein or only toxic RNA or only protein. They then introduced them into the nerve cells of fruit flies, which can undergo neurodegeneration in a similar way to humans. Repeat segments that made both RNA and protein caused striking neurodegeneration and reduced the lifespan of the flies, showing that they are a good organism in which to study these diseases. Interestingly, the protein-only repeat segments caused just as bad a neurodegeneration. In contrast, the RNA-only segments were harmless, pinpointing the role of toxic proteins in these diseases. The proteins that contained arginine were the most toxic. Max Planck Society