Personalised prognostic tools and gene-based therapies may improve the survival and quality of life of patients suffering from glioblastoma, an aggressive and deadly form of brain cancer, reports a new University of Illinois study funded by the NIH National Cancer Institute.
‘We confirmed known biomarkers of glioblastoma survival and discovered new general and clinical-dependent gene profiles,’ said Nicola Serao, a U of I Ph.D. candidate in animal sciences with a focus in statistical genomics. ‘We were able to compare biomarkers across three glioblastoma phases that helped us gain insight into the roles of genes associated with cancer survival.’
Glioblastoma is a complex, multifactorial disease that has swift and devastating consequences, Serao said. Although some genes have been associated with the presence of glioblastoma, few have been identified as prognostic biomarkers of glioblastoma survival and fewer have been confirmed in independent reports.
‘You can’t just find one gene that is related to this cancer and fix it,’ he said. ‘This is one of the aspects of our research that makes it unique. We were able to look at several genes at the same time and relate our findings to this cancer.’
Using genomic information from more than 22,000 genes, Serao took this huge piece of information and began slicing away at it, one gene at a time, until he ended up with a group of genes related to brain cancer.
He studied different survival variables, including length of survival from birth to death, from diagnosis to death, and from diagnosis to progression of the cancer.
‘We studied different variables, but they were complementary, and allowed us to learn more about those genes,’ he said. ‘We understand that some genes have much more impact in cancer than others. And we also discovered that some genes only appeared in one variable, so they were specific for a given phase of cancer.’
This study not only evaluated genes influencing survival, but also took into consideration clinical factors such as age, race and gender.
‘Our research suggests you can’t treat all patients the same,’ Serao said. ‘For example, we found gene expression patterns that have different, and sometimes opposite, relationships with survival in males and females and concluded that treatments affecting these genes will not be equally effective. Personalised therapy dependent on gender, race and age is something that is possible today with our advanced genomic tools.’
Recognising that genes seldom act alone, this team of researchers took several genes into consideration at the same time and uncovered networks of genes related to glioblastoma survival.
Sandra Rodriguez Zas, co-researcher and U of I professor of animal science and bioinformatics, said they looked at commonalities between the genes linked to glioblastoma survival and progression, too.
‘If a large number of genes linked to survival belong to a particular pathway, this pathway is considered enriched,’ Rodriguez Zas said. ‘Depending on whether the pathway and genes have tumour suppressor or oncogenic characteristics, we should be able to use that information to support or attack that pathway with targeted therapies.’
Gaining a deeper understanding of the biological meaning, or roles, for these genes will provide researchers with even more ammunition to fight this deadly form of brain cancer.
‘Because of the innovative approach we used, we believe we can more confidently predict whether a patient will have a shorter or longer survival rate and select the most adequate therapies,’ she said.
Illinois. University of Illinois College of Agricultural, Consumer and Environmental Sciences

Certain proteins, such as 14-3-3, conserve their basic functions of cell cycle control in diverse organisms, from worms to humans. In a study led by Julián Cerón and Simó Schwartz Jr, researchers from the Bellvitge Biomedical Research Institute (IDIBELL) and the Research Institute of Vall d’Hebron (VHIR) respectively, have described germ line functions of par-5, which is one of the two 14-3-3 proteins existing in Caenorhabditis elegans, worms used as experimental model in genetic studies. The overexpression of the 14-3-3 proteins is related to the resistance of tumours to chemotherapy, which could have implications for clinical practice.
Researchers found that par-5 gene, as its human homologues, is required for DNA damage response in C. Elegans validating the model to investigate chemotherapies and genetic modifications since 14-3-3 proteins are therapeutic targets in cancer
The powerful genetic tools of C. elegans have allowed a precise functional dissection of the single 14-3-3 protein present in their germline. The researchers have discovered that par-5 is not only necessary for proper cell cycle regulation, but also to prevent the accumulation of endogenous DNA damage and genomic instability.
Moreover, this study reveals that par-5 is required for DNA repair response when it is damaged by chemicals or ionizing radiation. In such response, the researchers propose a model where PAR-5 regulates CDK-1 phosphorylation to stop the cell cycle and repair the damage induced by chemotherapeutic agents.
The overexpression of the 14-3-3 protein has been related to chemotherapy resistance in cancer cell lines while its downregulation sensitises cells to therapy-induced cell death. Therefore, this study in C. elegans provides the basis for a model to study chemotherapy response in the context of a whole living organism.
Regulators proteins 14-3-3, evolutionarily conserved, bind to signalling proteins and affect their stability, activity or cellular localisation. So, they are involved in the regulation of various cellular processes, including apoptosis, the cell cycle and stress response.
In addition, the researchers found that par-5 is required for cell cycle arrest in response to replicative stress and ionizing radiation. IDIBELL-Bellvitge Biomedical Research Institute

Retinoic acid (vitamin A) and steroids are hormones found in our body that protect against oxidative stress, reduce inflammation and are involved in cellular differentiation processes. One of the characteristics of tumours is that their cells have lost the ability to differentiate; therefore these hormones have useful properties to prevent cancer. Currently, retinoic acid and steroids are being used to treat some types of leukemia.
A study led by the research group on Genes and Cancer of the Bellvitge Biomedical Research Institute (IDIBELL) has shown that loss of BRG1 gene implies a lack of response of cells to these hormones, and therefore the tumour may continue growing.
The IDIBELL research group on Genes and Cancer led by Montse Sanchez-Cespedes discovered some years ago that the BRG1 gene, a tumour suppressor, is inactivated in non-small cell lung cancer by genetic mutations. ‘The BRG1 protein is part of a chromatin remodelling complex that regulates the expression of several genes,’ said the researcher, ‘and is related to the differentiation of lung cells, allowing cells response to certain hormones and environment vitamins like vitamin A or steroids.’
When BRG1 is mutated and therefore inactive, tumour cells do not respond to the presence of these hormones and they continue growing and spreading. For this reason, these types of tumours are refractory to treatment with these substances.
‘At the moment,’ says Montse Sanchez-Cespedes, ‘we are not able to restore the functionality of a tumour suppressor gene as BRG1 in patients. Therefore, we are still far from a therapeutic application but the discovery enables us to better understand the biology of tumours. What we will try to do in the immediate future is to look for agents that specifically destroy the cells with mutated BRG1, following the strategy of lethal synthetics’.
In any case, this finding it can be useful in advancing personalised medicine, because ‘it explains why lung cancer patients are resistant to these treatments and may serve to rule out therapies with lipid-derived hormones in patients with BRG1 mutations, not just in lung cancer but also in breast and prostate, among others. ‘ IDIBELL

Biomedical engineers at UC Davis have developed a microfluidic chip to test for latent tuberculosis. They hope the test will be cheaper, faster and more reliable than current testing for the disease.
‘Our assay is cheaper, reusable, and gives results in real time,’ said Ying Liu, a research specialist working with Professor Alexander Revzin in the UC Davis Department of Biomedical Engineering.
The team has already conducted testing of blood samples from patients in China and the United States.
About one-third of the world’s population is infected with the bacteria that cause tuberculosis, a disease that kills an estimated 1.5 million people worldwide every year, according to the U.S. Centers for Disease Control and Prevention.
Most infected people have latent TB, in which the bacteria are kept in check by the immune system. Patients become sick only when the immune system is compromised, enabling the bacteria to become active. People with HIV are at especially high risk.
Current tests for latent TB are based on detecting interferon-gamma, a disease-fighting chemical made by cells of the immune system. Commercially available tests require sending samples to a lab, and can be used just once.
Liu and Revzin used a novel approach: They coated a gold wafer with short pieces of a single-stranded DNA segment known to stick specifically to interferon-gamma. They then mounted the wafer in a chip that has tiny channels for blood samples. If interferon-gamma is present in a blood sample, it sticks to the DNA, triggering an electrical signal that can be read by a clinician.
‘If you see that the interferon-gamma level is high, you can diagnose latent TB,’ Liu said.
The researchers plan to refine the system so that the microfluidic sensor and electronic readout are integrated on a single chip. UC Davis

The use of genome-wide array analysis in parents whose children are suspected of having a genetic disease shows that the parents frequently also have previously undetected genetic abnormalities, a researcher from The Netherlands told the annual conference of the European Society of Human Genetics. Being aware of this is important to parents because it means that their risk of having another affected child is significantly increased.
Dr. Nicole de Leeuw, a clinical laboratory geneticist in the Department of Human Genetics of the Radboud University Nijmegen Medical Centre in Nijmegen, and colleagues performed genome-wide SNP array analysis in 6,500 patients and 1,874 parents. The patients had intellectual disability and/or congenital abnormalities, and the parents of those in whom an aberration was detected were tested in a similar way to determine whether they had the same aberration as their child. Mosaic aberrations, where both genetically normal and abnormal cells are present in an individual, were not only found in one in every 300 patients, but in one in every 270 parents as well. ‘These abnormalities occurred more frequently than we had expected’, said Dr. de Leeuw. ‘Armed with this knowledge, we can try to understand not only why, but also how genetic disease arises in individuals, and this can help us to provide better genetic counselling.’
Analysis of patients’ genomes showed 6.5% de novo (spontaneously arising) genomic imbalances, 9.1% of rare, inherited imbalances, and 0.8% of X-linked abnormalities. Moreover, with the additional data from their SNP array test results, the researchers were able to subsequently find pathogenic mutations in recessive disease genes, uniparental disomies (where a single chromosome is doubled leading to two genetically identical ones), and mosaic aneuploidies (an extra or missing chromosome in some of the cells of the body) in about 30 patients.
‘In at least seven families, these findings meant that what we had thought of as a spontaneously arising, non-inherited genetic abnormality in a child was in fact already present in some form in the parent’, said Dr. de Leeuw. ‘Furthermore, when we tested in different cell lines – for example, DNA from blood and that from a mouth swab – we often found that results varied. This is because mosaic aberrations can occur in cells in some organs and not in others, and underlines the importance of not just relying on one type of cell line for this kind of genetic diagnosis.’
In two cases these tissue-dependent differences changed over time, and the researchers believe that this was due to an attempt by the body to correct and rescue the situation. ‘Such rescue attempts are best known in cases of trisomy, where there are three chromosomes instead of two in a cell, or monosomy, where there is only one. In both these cases, the body may try to correct the situation by respectively deleting or adding (doubling) a chromosome. Such rescue mechanisms may be more common than we expected, and by using genome-wide SNP array analysis it will help us to reveal them. For some patients, it would be particularly interesting if we could test multiple samples of these patients over time’, said Dr. de Leeuw. EurekAlert