Using next generation gene sequencing techniques, cancer researchers at UT Southwestern Medical Center have identified more than 3,000 new mutations involved in certain kidney cancers, findings that help explain the diversity of cancer behaviours.

 “These studies, which were performed in collaboration with Genentech Inc., identify novel therapeutic targets and suggest that predisposition to kidney cancer across species may be explained, at least in part, by the location of tumour suppressor genes with respect to one another in the genome,” said Dr. James Brugarolas, Associate Professor of Internal Medicine and Developmental Biology, who leads UT Southwestern’s Kidney Cancer Program at the Harold C. Simmons Cancer Center.

More than 250,000 individuals worldwide are diagnosed with kidney cancer every year, with lifetime risk of kidney cancer in the US estimated at 1.6 percent. Most kidney tumours are renal cell carcinomas, which when metastatic remain largely incurable.

Researchers with UT Southwestern’s Kidney Cancer Program had previously identified a critical gene called BAP1 that is intimately tied to kidney cancer formation. Their latest research shows how BAP1 interacts with a second gene, VHL, to transform a normal kidney cell into a cancer cell, which in part appears to be based on the two gene’s close proximity in humans, said Dr. Brugarolas, a Virginia Murchison Linthicum Endowed Scholar in Medical Research.

The newest findings suggest that the transformation begins with a mutation in one of the two copies of VHL, which is the most frequently mutated gene in the most common form of kidney cancer, clear cell type, which accounts for about 75 percent of kidney cancers. The VHL mutation is followed by a loss of the corresponding chromosome arm containing the second copy of VHL, as well as several other genes including PBRM1 and BAP1. This step eliminates the remaining copy of VHL and along with it, one of the two copies of PBRM1 and BAP1, two important genes that protect the kidney from cancer development. The subsequent mutation of the remaining copy of BAP1 leads to aggressive tumours, whereas mutation of the remaining copy of PBRM1 induces less aggressive tumours, said Dr. Payal Kapur, a key investigator of both studies who is an Associate Professor of Pathology and Urology, and the Pathology co-Leader of the Kidney Cancer Program.

This model also explains why humans born with a mutation in VHL have a high likelihood of developing kidney cancer during their life time. In these individuals, all kidney cells are already deficient for one VHL copy and a single deletion eliminates the second copy, along with a copy of BAP1 and PBRM1. In contrast, in other animals, these three genes are located on different chromosomes and thus more mutational events are required for their inactivation than in humans. Consistent with this notion, when UT Southwestern researchers mutated VHL and BAP1 together, kidney cancer resulted in animals.

In a second collaborative study with Genentech Inc., published in Nature Genetics, investigators implicated several genes for the first time in non-clear cell kidney cancer, a less common type that accounts for about 25 percent of kidney cancers. Researchers identified a gene signature that can help differentiate subtypes of non-clear cell tumours to better define their behaviour. Specifically, the researchers characterized alterations from 167 human primary non-clear cell renal cell carcinomas, identifying 16  significantly mutated genes in non-clear cell kidney cancer that may pave the way for the development of novel therapies. The research team also identified a five-gene set that enabled molecular classifications of tumour subtypes, along with a potential therapeutic role for BIRC7 inhibitors for future study.     UT Southwestern Medical Center

Despite a strong suspected link between genetics and asthma, commonly found genetic mutations account for only a small part of the risk for developing the disease — a problem known as missing heritability.

Rare and low frequency genetic mutations have been thought to explain missing heritability, but it appears they are unlikely to play a major role, according to a new study led by scientists from the University of Chicago. Analysing the coding regions of genomes of more than 11,000 individuals, they identified mutations in just three genes that were associated with asthma risk. Each was associated with risk in specific ethnicities.

‘Previous studies have likely overestimated the heritability of asthma,’ said study senior author Carole Ober, PhD, Blum-Riese Professor and chair of the Department of Human Genetics at the University of Chicago. ‘This could be because those estimates are based on correlations between family members that share environment as well as genes, which could inflate the heritability. Gene-environment interactions are not considered in these large scale association studies, and we know that these are particularly important in establishing individual risks for asthma.’

Asthma affects more than 25 million adults and children of all ages and ethnicities in the US. Due to the widespread nature of the disease, most studies of its genetic underpinnings have focused on commonly occurring mutations, referred to as genetic variants. However, while numerous such variants have been identified, they are able to account for only a small proportion of the risk for inheriting or developing asthma. Rare mutations, found in less than five percent of the population, have been hypothesized to explain this disparity.

Graduate student Catherine Igartua led the analysis under the supervision of co-senior author Dan Nicolae, PhD, Professor in the Departments of Medicine, Statistics and Human Genetics. She evaluated nearly 33,000 rare or low frequency mutations in more than 11,000 individuals of a variety of ethnicities representing European, African and Latino backgrounds. She analysed mutations jointly across subjects, using a technique that allowed them to study mutations common in one ethnicity, but rare in others.

Only mutations in the genes GRASP, GSDMB and MTHFR showed a statistical link to asthma risk. Mutations in the first two genes were found primarily in Latino individuals, and mutations in the last gene in those with African ancestry. These genes, involved in protein scaffolding, apoptosis regulation and vitamin B9 metabolism respectively, have as yet unknown roles in asthma. The rarity and ethnic-specificity of these genes is insufficient to account for the widespread prevalence of asthma.

Although rare mutations might not contribute much to population asthma risk, these genes still have the potential to serve as targets for therapeutic development. Ober points to the discovery of rare mutations in the LDL receptor that eventually led to the development of statins to treat high cholesterol. She also notes that it is possible, but unlikely, that there are mutations with large effects on asthma risk outside of their screen as it looked at approximate 60 percent of mutations in coding regions of the genome.

‘It was assumed that there would be rare mutations with larger effect sizes than the common variants we have been studying,’ Ober said. ‘Surprisingly, we found that low frequency mutations explain only a very small amount of asthma risk.’ The University of Chicago Medicine

Scientists at IRB Barcelona have observed that, when deprived of food, flies that do not express p53 show poor management of energy store.

The study further supports the involvement of this molecule—traditionally associated with tumour suppression—in metabolism.

The researchers provide new insights to study p53 function in metabolic diseases such as diabetes and obesity. Most scientific literature devoted to the protein p53 refers to cancer biology, and the functions of this molecule as a tumour suppressor have been described in detail. Furthermore, also in cancer biology, it is known that p53 inhibits the metabolic pathways of tumour cells in order to block their metabolism and prevent their rapid growth and proliferation.

The most innovative research on p53 attempts to unveil its functions in the management of energy stores and nutrients in healthy cells. Recent studies with cell cultures have demonstrated that p53 is activated in response to nutrient depletion. This observation thus opens up a promising field of research into the role of p53 in metabolism and cell health.

This is precisely the field tackled in a study performed by scientists headed by ICREA Research Professor Marco Milán, at the Institute for Research in Biomedicine (IRB Barcelona). In this work, the authors show that in the fly Drosophila melanogaster p53 is activated in certain cells to adapt the metabolic response to nutrient deprivation, thus having a global effect on the organism.

The researchers also reveal the molecular mechanisms through which the activity of p53 is regulated. The results obtained in Drosophila are useful to address the study of the molecular mechanisms of p53 in vertebrate models and to examine whether this protein is involved in diabetes and obesity.

In humans, nutrient management is organised by a coordinated system involving cells from adipose tissue and from organs such as the pancreas and liver. When we eat, a complex system is triggered in which the hormones insulin and glucagon are responsible for distributing nutrients among tissues and storing them for later use. In Drosophila the storage and management of energy is regulated by cells from a tissue known as the fat body.

“Through this study we demonstrate that Drosophila is useful to study the adaptive response of an organism to the presence or absence of food and to examine the systemic response. In addition, this model contributes to revealing the molecular mechanisms activated and that work in the same way in vertebrates,” explains Milán, head of the Development and Growth Control Lab at IRB. “In fact, we can now generate diabetic and obese flies to study these metabolic diseases at the molecular level.”

p53 allows energy use to be adjusted in order to optimise energy stores

The scientists studied the function of p53 in fasting flies in order to unveil the metabolic response of the organism. When no food is available, p53 is activated exclusively in cells of the fat body. The activity of this protein induces a change in the metabolism of these cells in such a way that they stop using glucose and make new nutrients to fuel the surrounding tissues.

“p53 acts as a sensor of the fat body of the fly. It makes cells “tighten their belts” in order to use energy stores prudently and makes them act unselfishly in order to ensure a supply to other cells,” describes Lara Barrio, first author of the article and a PhD student in Marco Milán’s lab. The key role of p53 in metabolism is reflected by the fact that flies in which p53 is inhibited die more quickly.

The team believes that this work with Drosophila will pave the way to more in-depth research into the biology and functions of p53 in metabolism and associated diseases. “It would be particularly interesting,” say the scientists, “to address vertebrates and analyse the participation of p53 in diabetes and obesity and the cardiovascular conditions associated with these metabolic disorders.” IRB Barcelona

A new diagnostic technology may significantly improve early detection and treatment of cancer and other diseases. Via a simple blood test the method can potentially diagnose diseases such as cancer at an early stage, enable screening of healthy individuals at risk of developing cancer, and help plan an individual course of treatment. Aarhus University has just received a patent for the technology in the USA.

‘The fact that we have now received patent protection for the American market is a really promising sign. We have just begun clinical research for breast cancer and the first results are very encouraging. We already know that the method can be used for many different types of cancer and potentially other diseases, but carrying out research that aims to develop diagnostic testing requires substantial funding,” says Tomasz K. Wojdacz, honorary associate professor at the Department of Biomedicine at Aarhus University, who together with Associate Professor Lise Lotte Hansen conducts research in the field of epigenetics with focus on DNA methylation.

The new method can easily be implemented in practice. Diagnostic tests based on the method can be performed in most of diagnostic laboratories, as they do not require special equipment.

‘The method detects specific changes affecting the pattern of genes, which are either active or silenced in a specific cell. The method is very sensitive and able to detect these changes in a limited number of cells, which is e.g. crucial for early diagnosis of cancer. It is well established that environmental factors play a role in changing this pattern of active and silenced genes, changes that may play a role in the onset of not only cancer but a long list of diseases including diabetes, cardiovascular and psychiatric diseases. Therefore, we see a huge potential for the use of the method we have developed,” explains Lise Lotte Hansen.

Lise Lotte Hansen and Tomasz K. Wojdacz are currently focusing on the application of the method in breast cancer risk screening and treatment but hope to soon be able to start clinical research targeting other types of cancer and diseases.

Of all the countries in the world, Denmark is the one with the highest incidence of breast cancer. According to preliminary results, a new test based on this technology makes it possible to find about 15 per cent of the women who are at risk of breast cancer.

“Most of our research currently focuses on using the method to identify healthy individuals with increased risk of developing disease in the future. Identification of these patients before they develop disease has significant benefits not only for the patients but also for the healthcare systems. It brings significant savings, as it is always cheaper to prevent disease than treat it,” says Tomasz K. Wojdacz.

The new technology was discovered by Tomasz K. Wojdacz and Lise Lotte Hansen and further developed by Tomasz K. Wojdacz in collaboration with the Peter MacCallum Cancer Centre, Melbourne, Australia. The application process for the US patent began in 2007 and was finalised this October when the patent protection was granted. Aarhus University