Cancer sequencing initiative discovers mutations tied to aggressive childhood brain tumors

 by Biomechanism 

St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project provides first evidence linking cancer to mutations in genes involved in DNA organization

Brain tumor

Researchers studying a rare, lethal childhood tumor of the brainstem discovered that nearly 80 percent of the tumors have mutations in genes not previously tied to cancer. Early evidence suggests the alterations play a unique role in other aggressive pediatric brain tumors as well.

The findings from the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP) offer important insight into a poorly understood tumor that kills more than 90 percent of patients within two years. The tumor, diffuse intrinsic pontine glioma (DIPG), is found almost exclusively in children and accounts for 10 to 15 percent of pediatric tumors of the brain and central nervous system.

“We are hopeful that identifying these mutations will lead us to new selective therapeutic targets, which are particularly important since this tumor cannot be treated surgically and still lacks effective therapies,” said Suzanne Baker, Ph.D., co-leader of the St. Jude Neurobiology and Brain Tumor Program and a member of the St. Jude Department of Developmental Neurobiology. She is a corresponding author of the study published in the January 29 online edition of the scientific journal Nature Genetics.

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DIPG is an extremely invasive tumor that occurs in the brainstem, which is at the base of the skull and controls such vital functions as breathing and heart rate. DIPG cannot be cured by surgery and is accurately diagnosed by non-invasive imaging. As a result, DIPG is rarely biopsied in the U.S. and little is known about it.

Cancer occurs when normal gene activity is disrupted, allowing for the unchecked cell growth and spread that makes cancer so lethal. In this study, investigators found 78 percent of the DIPG tumors had alterations in one of two genes that carry instructions for making proteins that play similar roles in packaging DNA inside cells. Both belong to the histone H3 family of proteins. DNA must be wrapped around histones so that it is compact enough to fit into the nucleus. The packaging of DNA by histones influences which genes are switched on or off, as well as the repair of mutations in DNA and the stability of DNA. Disruption of any of these processes can contribute to cancer.

Researchers said that the mutations seem unique to aggressive childhood brain tumors.

“It is amazing to see that this particular tumor type appears to be characterized by a molecular ‘smoking gun’ and that these mutations are unique to fast-growing pediatric cancers in the brain,” said Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis and one of the study’s corresponding authors. “This is exactly the type of result one hopes to find when studying the genomes of cancer patients.”

The results are the latest from the PCGP, an ambitious three-year effort to sequence the complete normal and cancer genomes of 600 children with some of the most poorly understood and aggressive pediatric cancers. The human genome includes the complete set of instructions needed to assemble and sustain human life. The goal is to identify differences that explain why cancer develops, spreads and kills. Researchers believe the findings will provide the foundation for new tools to diagnose, treat or prevent the disease.

For this study, researchers sequenced the complete normal and cancer genomes of seven patients with DIPG. “The mutations were found at such high frequency in the cancer genomes of those seven patients that we immediately checked for the same alterations in a larger group of DIPGs,” Baker said. When researchers sequenced all 16 of the related genes that make closely related variants of histone H3 proteins in an additional 43 DIPGs, they found many of the tumors contained the same mistakes in only two of these genes.

Of the 50 DIPG tumors included in this study, 60 percent had a single alteration in the makeup of the H3F3A gene. When the mutated gene was translated into a protein, the point mutation led to the substitution of methionine for lysine as the 27th amino acid in this variant of histone H3 protein. Another 18 percent of the DIPG patients carried the same mistake in a different gene, HIST1H3B.

Researchers are now working to understand how mutations in H3F3A and HIST1H3B impact cell function and contribute to cancer. Earlier research provides some clues. The lysine that is mutated is normally targeted by enzymes that attach other molecules to histone H3, influencing how it interacts with other proteins that regulate gene expression, Baker said. Mutations in the enzymes that target histone H3 have been identified in other cancers, but this is the first report showing a specific alteration of histones in cancer.

H3F3A and HIST1H3B were also mutated in other aggressive childhood brain tumors, glioblastoma, that develop outside the brain stem. Of 36 such tumors included in this study, 36 percent carried one of three distinct point mutations in the genes. The alterations included another single change in the makeup of H3F3A not found in DIPGs.

The histone H3 genes, however, were not mutated in any of the 252 other childhood tumors researchers checked for this study. The list included the brain tumors known as low-grade gliomas, medulloblastomas and ependymomas plus other cancers outside the brain and nervous system. The H3 changes have not been reported in any other cancers, including adult glioblastoma. “This suggests these particular mutations give a very important selective advantage, particularly in the developing brainstem and to a lesser degree in the developing brain, which leads to a terribly aggressive brain tumor in children, but not in adults,” Baker said.

“This discovery would not have been possible without the unbiased approach taken by the Pediatric Cancer Genome Project,” Baker said. “The mutations had not been reported in any other tumor, so we would not have searched for them in DIPGs. Yet the alterations clearly play an important role in generating this particular tumor.”

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Courtesy St. Jude Children’s Research Hospital 

childhood brain tumors

cancer sequencing 

DNA organization

A mutant protein linked to pancreatic cancer growth, new study finds

 by Biomechanism 

A mutant protein found in nearly all pancreatic cancers plays a role not only in the cancer’s development but in its continued growth, according to a new study from University of Michigan Comprehensive Cancer Center researchers. The finding suggests a possible target for developing new ways to treat this deadly disease.

Researchers have known that mutations in the Kras gene are what cause pancreatic cancer to develop. These mutations are frequently seen in common precancerous lesions, suggesting it has an early role in pancreatic cancer.

The new study, published in the February Journal of Clinical Investigation, finds that in mice, mutant Kras also keeps the tumor growing and helps precancerous tumors grow into invasive cancer. When the researchers turned off Kras, the tumors disappeared and showed no signs of recurring.

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The researchers were able to manipulate Kras in a mouse model that they designed to look at Kras at various points in pancreatic cancer development. In the precancerous lesions, turning off Kras eliminated the tumors in mice and the pancreas tissue returned to normal, with no signs of the cancer returning. With invasive cancer, inactivating Kras killed off the cancer but left the pancreas with fibrous areas similar to scar tissue. Tumors did not recur.

Researchers hope this finding provides the basis for future drug development.

“Right now no drugs specifically target Kras, but there are drugs that target the cellular processes downstream of Kras. We next need to figure out which of these downstream effectors of Kras are important in pancreatic cancer,” says study author Marina Pasca di Magliano, Ph.D., assistant professor of surgery and of cell and developmental biology at the U-M Medical School.

Kras is also known to play a role in lung and colon cancer. But it is likely the biggest player in pancreatic cancer, where more than 90% of all tumors have mutated Kras. Pancreatic cancer is one of the most deadly types of cancer: about 4% of patients are alive five years after their diagnosis. The disease is often diagnosed when surgery is not an option and it tends to be resistant to available chemotherapies.

“There is a dire need for new therapies for pancreas cancer based on a better understanding of the biology of this disease. My lab is now looking at the downstream inhibitors of Kras to try to find the best target,” Pasca di Magliano says.

What is Kras? 

Kras are activating mutations that result in continual signal transduction, stimulating downstream signaling pathways involved in cell growth, proliferation, invasion, and metastasis. They have been observed in a variety of cancers.

Note to patients:

This research was based in mice and needs further testing before any possible treatments are available for clinical trials. For information about current pancreatic cancer treatments, call the U-M Cancer AnswerLine at 800-865-1125.

Pancreatic cancer statistics:

43,140 Americans will be diagnosed with pancreatic cancer this year and 36,800 will die from the disease, according to the American Cancer Society.

Additional authors: Meredith A. Collins, Filip Bednar, Yaqing Zhang, Jean-christophe Brisset, Stefanie Galban, Craig J. Galban, Sabita Rakshit, and Karen S. Flannagan, all from U-M; and N. Volkan Adsay from Emory University.

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Courtesy University of Michigan Cancer Center

New target for cancer therapy identified, preclinical study shows

 by Biomechanism 

An enzyme called tryptophan 2,3-dioxygenase or TDO enables tumors to avoid detection and rejection by the immune system 

Scientists from the Ludwig Institute for Cancer Research (LICR) in Brussels identified a new target for cancer therapy, an enzyme which prevents the immune system from recognizing and destroying certain types of tumors. Called tryptophan 2,3-dioxygenase or TDO, the enzyme works by depriving immune cells of tryptophan, an amino acid essential to their activity. TDO is produced by a significant number of human tumors.

Scientists also show that blocking TDO activity with a novel TDO inhibitor promotes tumor rejection in mice. The study findings were published online today in the January 30 issue of the Proceedings of the National Academy of Sciences (PNAS).

Cancer immunotherapy — leveraging the body’s own immune system to attack and destroy tumors — is emerging as a promising method for cancer treatment. Clinical testing of several immunotherapeutic approaches has shown variable success. Tumors often develop survival mechanisms to prevent the attack from the immune system. Researchers are now looking to evaluate the mechanisms that enable these tumors to escape detection by the immune system.

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Previously, Brussels scientists from LICR and the de Duve Institute at the Université catholique de Louvain (UCL) studied one enzyme that proved to do just that. It is known as indoleamine 2,3 dioxygenase or IDO1 for short. IDO1 is expressed in many cancers, including prostate, colon, pancreas and cervical tumors. IDO1 blocks the immune system’s ability to reject those tumors, by depriving immune cells of tryptophan.

In the PNAS study released today, the same Belgian researchers have shown that TDO is also expressed in various human tumors and degrades tryptophan in a similar manner. Tumors expressing TDO include bladder and liver cancers, as well as melanomas.

“Little is known about the TDO enzyme and its ability to trick the immune system and prevent it from destroying deadly tumors. Our research is the first to explore this relationship,” said study lead investigator, Benoit J. Van den Eynde, M.D., Ph.D., Brussels Branch Director at LICR.

The group studied a series of 104 human tumor lines of different types to confirm the activity of TDO in tumor cells. They learned that 20 tumors expressed TDO only, 17 others expressed IDO1 only and 16 expressed both. The findings suggest that TDO and IDO1 enzymes represent complementary cancer immunotherapy targets, which if blocked could potentially impact 51% of all tumors.

Demonstrating TDO Expression and Its Role in Thwarting Immune Attack

Knowledge: The colon is shaped like a tube, and is made up of several layers starting with the innermost layer, the mucosa (which is made up of epithelium), and then the lamina propria and muscularis mucosa. This is surrounded by the submucosa, which is surrounded by two layers of muscle (or muscularis), and finally, the serosa layer, which is the outside layer of the tube. The outside of the colon is covered with a layer of fat, also called adipose tissue, which contains lymph nodes and blood vessels which feed the colon tissue.

Using a validated mouse tumor model, researchers established that TDO expression caused tumor cells to resist immune rejection. They first vaccinated the mice with an antigen that caused them to reject the tumor. Then they injected TDO-expressing tumor cells into the immunized mice. Researchers found that immunized mice no longer rejected the TDO-expressing tumors. This demonstrated that the presence of TDO prevented the immune system from attacking tumors.

In collaboration with scientists from the University of Namur (Belgium), the team then developed an active compound to inhibit TDO enzymatic activity. “Our study showed quite beautifully that the TDO inhibitor restored the ability of mice to reject tumors despite the presence of TDO in tumor cells,” said Dr. Van den Eynde.

Research recently published in the October 6, 2011 issue of Nature (Opitz, C.A. et al.) validates today’s study results by showing that TDO expression in human glioblastomas promotes tumor progression.

Toward Clinical Development of a TDO-inhibitor

The research team is moving forward to validate TDO inhibition in other preclinical models. Working closely with LICR colleagues in San Diego, the team will also conduct high-throughput screening to find a more stable TDO-inhibitor compound that can be advanced in clinical testing.

LICR plans, conducts, administers, and sponsors its own clinical trials as part of its technology development process. This process allows basic investigations to continue into early stage clinical evaluation of a new therapy, and makes the clinic an essential arm of the research enterprise.

“We will continue to search for inhibitors of TDO, an important new clinical target,” confirmed Jonathan Skipper, Ph.D., Executive Director, Technology Development at LICR. “LICR intends to license its discovery to a new commercial enterprise in the near future.”

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NOTE: For further information on this study, please contact Rachel Steinhardt, rsteinhardt@licr.org or 212-450-1582. 

From mice to elephants

MONASH UNIVERSITY

"It takes 24 million generations for a mouse-sized animal to evolve to the size of an elephant." Image: Kerrick/iStockphoto Scientists have for the first time measured how fast large-scale evolution can occur in mammals, showing it takes 24 million generations for a mouse-sized animal to evolve to the size of an elephant. Research published today in the Proceedings of the National Academy of Sciences USA (PNAS) describes increases and decreases in mammal size following the extinction of the dinosaurs 65 million years ago. Led by Dr Alistair Evans of Monash University's School of Biological Sciences a team of 20 biologists and palaeontologists discovered that rates of size decrease are much faster than growth rates. It takes only 100,000 generations for very large decreases, leading to dwarfism, to occur. Dr Evans, an evolutionary biologist and Australian Research Fellow, said the study was unique because most previous work had focused on microevolution, the small changes that occur within a species. “Instead we concentrated on large-scale changes in body size. We can now show that it took at least 24 million generations to make the proverbial mouse-to-elephant size change – a massive change, but also a very long time,” Dr Evans said. "A less dramatic change, such as rabbit-sized to elephant-sized, takes 10 million generations." The paper looked at 28 different groups of mammals, including elephants, primates and whales, from various continents and ocean basins over the past 70 million years. Size change was tracked in generations rather than years to allow meaningful comparison between species with differing life spans.  Dr Erich Fitzgerald, Senior Curator of Vertebrate Palaeontology at Museum Victoria and a co-author, said changes in whale size occurred at twice the rate of land mammals. “This is probably because it’s easier to be big in the water – it helps support your weight,” Dr Fitzgerald said. Dr Evans said he was surprised to find that decreases in body size occurred more than ten times faster than the increases. “The huge difference in rates for getting smaller and getting bigger is really astounding – we certainly never expected it could happen so fast!” Dr Evans said. Many miniature animals, such as the pygmy mammoth, dwarf hippo and ‘hobbit’ hominids lived on islands, helping to explain the size reduction. “When you do get smaller, you need less food and can reproduce faster, which are real advantages on small islands,” Dr Evans said. The research furthers understanding of conditions that allow certain mammals to thrive and grow bigger and circumstances that slow the pace of increase and potentially contribute to extinction. Editor's Note: Original news release can be found here

Minds can affect illness: study

THE UNIVERSITY OF AUCKLAND

Illness perceptions can be associated with emotional distress, recovery, disability and more.  Image: MarsBars/iStockphoto What you think about your illness matters just as much, if not more, in determining your health according to a new report by researchers from The University of Auckland and King’s College London. The paper “Patients’ perceptions of their illness: The dynamo of volition in health care” which reviews many studies examining the impact of perception on health was published in the Association in Psychological Science journalCurrent Directions in Psychological Science this week. Findings show that people’s perceptions about their illness bear a direct relationship to several important health outcomes, including how well they are able to function, their use of health care, adherence to treatment plans, the duration of the illness and even mortality. Moreover, some research suggests that how a person views their illness may play a bigger role in determining their health outcomes than the actual severity of the disease. The review shows that illness perceptions change rapidly in response to diagnostic results and can be associated with emotional distress, recovery, and disability, as well as with treatment-related behaviour such as adherence. Lead author Professor Keith Petrie from The University of Auckland’s Department of Psychological Medicine says: “In general, our illness perceptions emerge out of our beliefs about illness and what illness means in the context of our lives. We might have beliefs about how an illness is caused, how long it will last, how it will impact us or our family, and how we can control or cure it. The bottom line is that patients’ perceptions of their illness guide their decisions about health. “This suggests that effective treatment is about much more than having a competent physician. A doctor can make accurate diagnoses and have excellent treatments but if the therapy doesn’t fit with the patient’s view of their illness, they are unlikely to keep taking it.” The authors suggest that simple interventions such as conversations between health professionals and patients which elicit what people really think about their illness might identify patients at risk of coping poorly with the demands of their illness, allow erroneous beliefs to be corrected and improve treatment regimes. “Examining patients’ perceptions opens up a new approach in modern medicine. Ultimately it could lead to more effective treatment.” Editor's Note: Original news release can be found here.

Study remaps how blood cells form

WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH

The findings can also help researchers discover new ways in which the progenitor cells can be controlled. Image: BlackJack3D/iStockphoto A study of the cells that respond to crises in the blood system has yielded a few surprises, redrawing the ‘map’ of how blood cells are made in the body. The finding, by researchers from the Walter and Eliza Hall Institute, could have wide-ranging implications for understanding blood diseases such as myeloproliferative disorders (that cause excess production of blood cells) as well as used to develop new ways of controlling how blood and clotting cells are produced. The research team, led by Drs Ashley Ng and Maria Kauppi from the institute’s Cancer and Haematology division, investigated subsets of blood ‘progenitor’ cells and the signals that cause them to expand and develop into mature blood cells. Their results were published in the journalProceedings of the National Academy of Sciences of the United States of America. Dr Ng describes blood progenitor cells as the ‘heavy lifters’ of the blood system. “They are the targets for blood cell hormones, called cytokines, which Professor Don Metcalf and colleagues have shown to be critical for regulating blood cell production,” Dr Ng said. “In times of stress, such as bleeding, during infection or after chemotherapy, it is really the progenitor cells that respond by replacing lost or damaged blood cells.” Dr Kauppi said the research team was particularly interested in myeloid progenitor cells, which produce megakaryocytes, a type of bone marrow cell that gives rise to blood-clotting platelets. “We used a suite of cell surface markers specific to these progenitor cells that allowed us to isolate and characterise the cells,” she said. The researchers were surprised to find that progenitor cells believed only to be able to produce megakaryocytes were also able to develop into red blood cells. “We were able to clearly demonstrate that these mouse megakaryocyte progenitor cells have the potential to develop into either megakaryocytes or red blood cells in response to cytokines such as thrombopoietin and erythropoietin, which was quite unexpected,” Dr Ng said. “In addition, we discovered that other progenitor populations thought to really only make neutrophils and monocytes [other immune cells], were capable of making red blood cell and platelets really well. In effect, we will have to redraw the map as to how red cells and platelets are made in the bone marrow.” Dr Kauppi said the researchers found they could regulate whether the progenitor cell became a megakaryocyte or a red blood cell by using different combinations of cytokines. “Now that we have properly identified the major cells and determined how they respond to cytokine signals involved in red blood cell and platelet production, the stage is set for understanding how these progenitors are affected in health and disease,” she said. “We can also better understand, for instance, how genetic changes may lead to the development of certain blood diseases. “ Dr Ng said the findings would also help researchers discover new ways in which the progenitor cells can be controlled. “This research is the first step in the future development of treatments for patients with blood diseases,” Dr Ng said. “This may occur either by limiting blood cell production when too many are being made, as with myeloproliferative disorders, or stimulating blood production when the blood system is compromised, such as during cancer treatment or infection.” Dr Ng said. Editor's Note: Original news release can be found here.

Mobile Phone Data Reveals Human Reproductive Strategies

The pattern of calls and texts between humans reveals how women invest more heavily in their main relationship than men; and how this changes as they age.

KFC 

Various studies have shown that the frequency of contact between individuals is a reliable indicator of the emotional link between them. So it should come as no surprise that the data from mobile phone calls is a potential treasure trove of information about the social lives of humans. 

But analyses of this data so far have been distinctly unspectacular. For example, the location data associated with phone calls has revealed various new intricacies in the movements of commuters. Interesting but hardly jaw-dropping.

That is set to change with the work of Vasyl Palchykov at the Aalto University School of Science in Finland and a few buddies including a couple of old hands in the form of Albert-László Barabási at Northeastern University and Robin Dunbar at the University of Oxford (of Dunbar's number fame). 

These guys have got hold of a corpus of mobile phone data relating to calls between 1.4 million women and 1.8 million men in an unspecified European country. Between them, these phone subscribers made almost 2 billion calls and sent almost half a billion text messages. In addition to the gender of each subscriber, Palchykov and co also managed to get their age as well. 

That's significant because it allows them to study not allow the pattern of calls between genders but the way this changes with age. 

They began by taking each subscriber and determining the age and gender of the person they werein contact with most frequently, second most frequently and so on. These, they assume, are the 'best' friend, second best friend and so on.

Then, they looked at how the 'best friends' changed as subscribers age. It turns out in general that between the ages of 18 and 40 or so, men and women have best friends of the opposite sex. Palchykov and co assume this reflects the general pattern of mating in society. Second best friends are generally of the same sex at this age.

But they tease the most interesting phenomena out of the fine detail in their dataset. They conclude for example that women are more focused on opposite-sex relationships than men are during the period of their lives when they are reproductively active. That indicates that women invest  more heavily in creating and maintaining their relationships than men.

As women age, their attention shifts from their spouse to younger females some 25 years or so younger. That's about equal to a generation gap and Palchykov and co assume these younger females are daughters. This attention shift also seems to equate to the arrival of grandchildren, when the older female again once again begins to invest more heavily.

While older women focus more heavily on younger females, older men maintain an even gender balance in the second best friends, presumably this reflects an equal attention between children of opposite sexes.

What's striking about this is how strongly female relationships are determined by their reproductive cycle. “Women’s gender-biases thus tend to be stronger than men’s, seemingly because their patterns of social contact are strongly driven by the changes in the patterns of reproductive investment across the lifespan,” say Palchykov and co.

Clearly, female reproductive strategies change more explicitly as they age, switching from mate choice to personal reproduction to parental investment and finally grandparental investment, particularly after they reach 40. 

However, the most dramatic conclusion from this work is about the pattern of social relationships that play the most important role in society. Palchykov and co say the tendency in the past has been to assume that father-son relationships dominate. 

By contrast, “our results tend to support the claim that mother-daughter relationships play a particularly seminal role in structuring human social relationships,” they say. 

This difference on the way the sexes invest in relationships is exactly what evolutionary biologists expect. But although previously suspected, it has proved particularly difficult to test. That's why this work is something of a landmark.

Clearly, the ability to study human relationships on such a vast scale opens up a host of new avenues for research in social and reproductive strategies.

In particular, this study looks only at the existence of links between people, not the the directional asymmetries in relationships or who initiates contact.  Palchykov and co leave that for another day.

There's a mountain of data ready to be mined on this. And clearly, there's gold in them thar hills.

Ref: arxiv.org/abs/1201.5722: Sex differences in intimate relationships 

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