Researchers pinpoint genetic connection to traumatic experience

Rutgers scientists have uncovered genetic clues as to why some mice no longer in danger are still fearful while others are resilient to traumatic experiences – knowledge that could help those suffering with crippling anxiety and PTSD.

"Our work with mice demonstrates how genes play a role in developing and extinguishing pathological fear like Post Traumatic Stress Disorder," says Gleb Shumyatsky, an associate professor in the Department of Genetics in the School of Arts and Sciences. "It is clear that previous life experiences are not the only cause of PTSD – genetic predispositions may make some people more sensitive and others more resilient to PTSD."

Since humans and animals register fear in the brain similarly, the discovery being reported today in the journal PLoS ONE, is an important step to understanding how genes work in the brain to control learning and memory as well as reactions to fearful and traumatic experiences.

In the study, mice bred missing either one of the two fear memory-related genes were trained to be afraid of the cage and a tone associated with a mild shock. Next, by repeatedly putting the mice in the training cage or presenting them with the tone – but now without the shock – the scientists taught them not to be afraid, a process called fear memory extinction. When extinction was performed using the fearful context, a training cage, the knockout mice behaved normally, similar to wild type control mice.

These same mutant mice acted quite differently, however, when they heard a quiet, fear-evoking tone that had previously been followed by the same shock. Mice bred without the gastrin-related peptide receptor (GRPR) gene were more fearful of the tone and froze up more often than normal mice, despite no longer being in danger of receiving a shock. By contrast, mice bred without the stathmin gene forgot that they had been afraid of the dangerous tones and stopped freezing.

Next, the scientists analyzed the neural activities of portions of the brain that deal with fear and anxiety in humans – the amygdala, hippocampus, and medial prefrontal cortex. What they discovered: Genetic evidence of a connection between the amygdala – the portion of the brain where unconscious fears are stored – and the prefrontal cortex, the area that enables animals and humans to inhibit excessive fear to better react to potential danger.

The "fearless" stathmin-deficient mice exhibited an increase in brain activity in the prefrontal cortex and a decrease in the amygdala. The opposite occurred in the timid, GRPR deficient mice that were overly afraid in spite of the fact that they were no longer in danger.

Shumyatsky says scientists need to continue identifying molecules involved in the neural circuits of the brain responsible for specific memories and behaviors in order to develop psychotherapeutic, pharmacological and genetic therapies to treat disabling anxiety disorders like PTSD which is estimated to affect 30 percent of combat veterans.

"The research suggests that there are different types of PTSD and that different medical treatments could be applied to treat the cue-related versus the context-related PTSD symptoms, Shumyatsky says.

Provided by Rutgers University

"Researchers pinpoint genetic connection to traumatic experience." February 1st, 2012. http://medicalxpress.com/news/2012-02-genetic-traumatic.html

 

Posted by
Robert Karl Stonjek

Blood test accurately distinguishes depressed patients from healthy controls

The initial assessment of a blood test to help diagnose major depressive disorder indicates it may become a useful clinical tool. In a paper published in the journal Molecular Psychiatry, a team including Massachusetts General Hospital (MGH) researchers reports that a test analyzing levels of nine biomarkers accurately distinguished patients diagnosed with depression from control participants without significant false-positive results.

"Traditionally, diagnosis of major depression and other mental disorders has been made based on patients' reported symptoms, but the accuracy of that process varies a great deal, often depending on the experience and resources of the clinician conducting the assessment," says George Papakostas, MD, of the MGH Department of Psychiatry, lead and corresponding author of the report. "Adding an objective biological test could improve diagnostic accuracy and may also help us track individual patients' response to treatment."

The study authors note that previous efforts to develop tests based on a single blood or urinary biomarker did not produce results of sufficient sensitivity, the ability to detect the tested-for condition, or specificity, the ability to rule out that condition. "The biology of depression suggests that a highly complex series of interactions exists between the brain and biomarkers in the peripheral circulation," says study co-author John Bilello, PhD, chief scientific officer of Ridge Diagnostics (http://www.ridgedx.com

 

), which sponsored the current study. "Given the complexity and variability of these types of disorders and the associated biomarkers in an individual, it is easy to understand why approaches measuring a single factor would not have sufficient clinical utility."

The test developed by Ridge Diagnostics measures levels of nine biomarkers associated with factors such as inflammation, the development and maintenance of neurons, and the interaction between brain structures involved with stress response and other key functions. Those measurements are combined using a specific formula to produce a figure called the MDDScore – a number from 1 to 100 indicating the percentage likelihood that the individual has major depression. In clinical use the MDDScore would range from 1 to 10.

The initial pilot phase of the study enrolled 36 adults who had been diagnosed with major depression at the MGH, Vanderbilt University or Cambridge Health Alliance in Cambridge, Mass., along with 43 control participants from St. Elizabeth's Hospital in Brighton, Mass. MDDScores for 33 of the 36 patients indicated the presence of depression, while only 8 of the 43 controls had a positive test result. The average score for patients was 85, while the average for controls was 33. A second replication phase enrolled an additional 34 patients from the MGH and Vanderbilt, 31 of whom had a positive MDDScore result. Combining both groups indicated that the test could accurately diagnose major depression with a sensitivity of about 90 percent and a specificity of 80 percent.

"It can be difficult to convince patients of the need for treatment based on the sort of questionnaire now used to rank their reported symptoms," says Bilello. "We expect that the biological basis of this test may provide patients with insight into their depression as a treatable disease rather than a source of self-doubt and stigma. As we accumulate additional data on the MDDScore and perform further studies, we hope it will be useful for predicting treatment response and helping to select the best therapies."

Papakostas adds, "Determining the true utility of this test will require following this small research study with larger trials in clinical settings. But these results are already providing us with intriguing new hints on how powerfully factors such as inflammation – which we are learning has a major role in many serious medical issues – contribute to depression." Papakostas is an associate professor of Psychiatry at Harvard Medical School.

Provided by Massachusetts General Hospital

"Blood test accurately distinguishes depressed patients from healthy controls." February 1st, 2012. http://medicalxpress.com/news/2012-02-blood-accurately-distinguishes-depressed-patients.html

 

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Robert Karl Stonjek

Severe, rapid memory loss linked to future, fatal strokes

Severe, rapid memory loss may be linked to -- and could predict -- a future deadly stroke, according to research presented at the American Stroke Association's International Stroke Conference 2012.

Researchers found that people who died after stroke had more severe memory loss in the years before stroke compared to people who survived stroke or people who didn't have a stroke.

"We're most surprised that people who died after strokes had such sharp memory declines years before stroke onset" said Qianyi Wang, the study's lead author and a graduate student at the Harvard University School of Public Health in Boston, Mass.

In the study, researchers examined 11,814 people age 50 years and older every two years for signs of declining memory. Study participants were stroke-free at enrollment and were followed up to 10 years. Participants continued in the study if they survived a stroke. They reported 1,820 strokes, including 364 individuals who died after stroke but before the next memory assessment. Average memory loss each year was compared for participants who remained stroke free; participants who survived a stroke, considering their memory loss might be different before and after stroke; and participants who had a stroke but did not survive.

The researchers used a standard word-recall list to measure memory loss. For participants whose memory loss became too severe to use the word lists, researchers interviewed spouses or other caregivers using a standardized assessment. Memory score is expressed in standard deviation units.

The average memory score each year dropped: 

• 0.078 points in those who didn't have a stroke while in the study;
• 0.137 points before stroke in those who later survived a stroke;
• 0.205 points before stroke in those who later died from stroke.

The people who survived a stroke had worse average memory even before the stroke compared to similar individuals who never had a stroke during follow-up. At the time of stroke, memory function dropped an average 0.321 points. This difference is about the same as the average memory decline associated with growing 4.1 years older among those who remained stroke free. Because of the large stroke-related declines, memory impairment was common among stroke survivors.

Increased memory loss may be linked to a higher risk of fatal stroke for several reasons, researchers said.

"People who die after stroke may have worse underlying disease prior to stroke. This suggests early disease is accumulating and that something is happening to these people before they are diagnosed with clinical stroke." said M. Maria Glymour, S.D., senior study author and an assistant professor at the Harvard School of Public Health. "However, memory impairment is associated with increased mortality regardless of stroke. Memory impairment may therefore make patients more vulnerable to death in the wake of the stroke, for reasons that are unrelated to stroke severity. We're not sure which is true and we can't tell with these analyses, but we hope to examine this in the future."

Studies are needed to determine whether the effects of stroke on memory differ for different groups of people; for example, these effects may vary depending on race, gender, geographic location and socioeconomic status.

"Even health conditions that are much more common at older ages may have roots earlier in life," Glymour said. "Your entire life course influences your health in old age."

Provided by American Heart Association

"Severe, rapid memory loss linked to future, fatal strokes." February 1st, 2012. http://medicalxpress.com/news/2012-02-severe-rapid-memory-loss-linked.html

 

Posted by
Robert Karl Stonjek

Obesity reduces the size of your brain

(Medical Xpress) -- New research from Uppsala University shows that a specific brain region linked to appetite regulation is reduced in elderly people who are obese. Poor eating habits over a lifetime may therefore weaken brain function that helps us to control our desire to eat. The findings are published in The International Journal of Obesity.

Researchers Samantha Brooks and Helgi Schiöth, of the Department of Neuroscience at Uppsala University, and researchers in London, showed in an earlier article published in BMC Psychiatry that excessive regulation of appetite in those with anorexia nervosa is linked to greater brain volume in the same region. This research also showed that in anorexic females, the more they restrained their eating, the larger this brain region was. 

  

In a new study, Samantha Brooks, together with colleagues from Uppsala University (Christian Benedict, Helgi Schiöth, Elna-Marie Larsson, Håkan Ahlström and Lars Lind) and researchers from other European universities, have now looked at which brain regions, involved in regulation of appetite, are altered in those with long term obesity. By means of magnetic imaging (MRI) the researchers studied the brains of 292 elderly males and females who were classified as consistently obese or normal weight over a five year period before and after the brain scan. In those suffering from obesity a reduction in the frontal part of the brain was found. The researchers further examined the effects of being obese on a brain function linked to self-regulation of food intake, and found cognitive deficits in those who where obese compared to those who were normal weight.

Samantha Brooks explains: “Those elderly people who were consistently obese over a five year period showed reduced frontal brain volume and deficits in a brain function that helps us to control our food intake. Obesity is on the increase in our modern societies, and while our research cannot determine whether obesity causes or is a consequence of reduced brain volume, in light of our previous research it suggests that if you don’t use your brain to think about what you eat, you may not only lose your waist line, but brain volume as well.”

More information: Brooks S et al. Late life obesity is associated with smaller global and regional gray matter volumes: a voxel-based morphometric study. International Journal of Obesity, in press.

Provided by Uppsala University

"Obesity reduces the size of your brain." February 1st, 2012. http://medicalxpress.com/news/2012-02-obesity-size-brain.html

 

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Robert Karl Stonjek

Changing The Subject Matter

 

“No one can check the thinking activities of a living being, nor the feeling, willing or working processes. But if one wants actual happiness, one must change the subject matter only. Instead of talking of the politics of a dying man, one might discuss the politics administered by the Lord Himself.” (Shrila Prabhupada, Shrimad Bhagavatam, 1.6.34 Purport)

This whole world is a product of God’s energy after all, so a blanket rejection of everything within it as being detrimental towards one’s spiritual aspirations is not a very wise policy. Though the human being has so many tendencies towards behavior that proves to be harmful in the end, the inclination to act needn’t be unnaturally checked. Rather, the same interests can be directed towards the inexhaustibly brilliant Vedic literature, which is full of enough variety to satisfy the inquisitive mind for many lifetimes. The hero in these documented accounts, the person who is the central focus of the pious behavior followed and the anger and rage of those who defy the established law codes, is none other than the Supreme Lord, whose spiritual form allows for an attachment that proves to be the most auspicious.

Can attachment be detrimental? What is wrong with having affection for something? Is not the human spirit meant to love? If you have attachment to something that will cause you harm in the end, then obviously the emotional fixation is not warranted. For instance, having a few drinks at home after work may cause a slight relaxed sensation, but should the person indulge in even more adult beverages due to that feeling, in the process developing an attachment so strong that they can’t go a single day without intoxication

 

, will they be benefitted by that behavior?

What about an attachment to a relationship, such as one involving romance or friendship? Fidelity to the relationship is certainly honorable, but basing attachment solely on bodily designations is flawed from the beginning, for the forms identified with must be renounced at some point in the future. Death is guaranteed for whoever takes birth, and whoever dies is guaranteed to take birth. The spirit soul, the essence of identity, is transcendental to these changes, but unless one knows how to identify with the self, the attachments they form will be based on temporary objects that must be parted with eventually. The stronger the attachment, the more painful the emotional fall at the time of separation.

In day-to-day affairs, there is a desire to hear about famous people. The news media profits from this desire. And the sentiments don’t necessarily have to be positive. Should there be a lascivious scandal on the campus of a university famous for its football program, the same figures previously adored and hailed as legends will be dragged down to the point that the newsmakers won’t settle until everyone hates the involved parties. Politics is arguably followed by the most number of people, for what a politician says and how they say it form the subject matter for the endless debates that take place both in print and television news media.

Should we not follow world events? If things are going on around us, why would we want to close our ears to them? The Vedas declare that the human form of body is the most auspicious, but not for its ability to form attachments to bodily relationships or famous figures described in the news. These tendencies indeed exist because of the properties of spirit, which from its constitution has a propensity to love. Love results in service, the kind which operates without motivation and interruption.

“The supreme occupation [dharma] for all humanity is that by which men can attain to loving devotional service unto the transcendent Lord. Such devotional service must be unmotivated [ahaituki] and uninterrupted [apratihata] to completely satisfy the self.” (Shrimad Bhagavatam

 

, 1.2.6)

Service to worldly entities always involves motivation, and interruption is guaranteed. The attraction to the dealings of worldly figures carries the motivation for some type of personal enjoyment, either the ability to praise and honor someone or the inverse of harboring hatred and resentment. A famous athlete is praised for being so good at what they do, but should they fall from grace through illicit relations with many women, they will be hated by the same fans.

Shrila Bhaktivinoda Thakura, a famous acharya on the Vedic teachings of Lord Chaitanya

 

, remarks that hatred is borne of the same loving spirit found within the soul. Indeed, every emotion is derived from the soul’s desire to love in a transcendental way. This cogent fact uncovers the secret to finding lasting happiness, felicity which continues beyond the current lifetime. As the human being is the only species capable of rationally reaching this conclusion through following instruction and thinking it over before fully accepting it within the mind, it is the most advanced species. A precious human birth thus should not go to waste.

How do we break the tendency for harboring attachment to the temporary, or asat? When reviewing the disciplines of spirituality to potentially take up, it is natural to look at the restrictions first. To follow a discipline means that one currently does not have discipline. This only makes sense after all. We attend school to get educated because we are initially uneducated. We get trained in a particular field if we lack the training. Similarly, we start to follow religious principles because we currently don’t follow them at all.

The more restrictions you impose, the less appealing your system will be to potential followers. In the ultimate system of religion

 

 known as bhakti-yoga, or devotional service

 

, the bona fide acharyas, when deciding to accept disciples, will impose a restriction on meat eating, gambling

 

, intoxication and illicit sex

 

. It should be noted that these prohibitions are not necessary for practicing bhakti, as the chanting

 

 of the holy names, “Hare Krishna Hare Krishna, Krishna Krishna, Hare Hare, Hare Rama Hare Rama, Rama Rama, Hare Hare

 

”, can be taken up by anyone at any stage in life. The famous brahmana Ajamila inadvertently recited the name of Narayana, which is another word for God, at the time of death and was rescued from punishment for his past sinful behavior. During the latter half of his life Ajamila did not follow the regulative principles, so he would not have been accepted as a disciple of a bona fide spiritual master

 

. Nevertheless, through past accumulated spiritual merits, he was fortunate enough to say the holy name while quitting the body, which thus guaranteed his salvation.

This incident reveals the end-goal of the human birth: to think of God at the time of death. The restrictions are put into place to make that happen. Obviously for someone who grew up eating meat it will be difficult to give up the practice at every meal. The same goes for abandoning intoxication for someone who enjoys it so much, but the focus on the positives in bhakti is more important. With enough immersion in transcendental service, the restrictions will take care of themselves, though they are still explicitly stressed and monitored to show what is required in a spiritual leader. If a preacher speaks on the superiority of being attached to God and no one else, if they have attachments to sinful behavior, how will their message resonate? Example is better than precept, so one who actually follows the principles they preach will be a more effective leader.

Lord Chaitanya

 

, the famous preacher incarnation of Godhead, took to the renounced order of life at a very young age precisely for this purpose. Imagine a twenty-four year old coming up to you and speaking about detachment, the endless existence of the spirit soul, and how one should abandon attachment to anything not directly related to Krishna, or God. Will we take such a youngster seriously? What could they possibly know anyway? But if the same person lives in the renounced order of life, they immediately become superior to others in terms of authority. After all, the person being preached to likely isn’t asannyasi, and even if they are, they probably didn’t take to the order at such a young age. Thus through following the regulative principles, one earns respect from others and gets their attention when speaking on the glories of bhakti.

If the restrictions are imposed and followed, the tendency towards hearing about famous figures will be there anyway. If we don’t watch the news, we’ll still want to hear about someone else. Luckily for us, the Supreme Lord, the object of sacrifice and penance, comes to earth every so often along with His closest associates. As a respectful guest of the land He owns, Lord Krishna

 

 takes part in activities which mimic those of the ordinary living entities. The difference is that Krishna’s tejas, or splendor, is impossible to fully cover up. His activities, which include His instructing others, are the most splendid, so marvelous that they are still talked about to this day.

Pick up a gossip paper that is more than a week old and it likely won’t be useful to you. The twitter feed from a month ago doesn’t have any relevant information because the news reported was meant to only pique the curiosity of someone looking for higher enjoyment, not to satisfy them. With Krishna’s activities, the enjoyment derived from hearing lasts for as long as the Supreme Lord’s stories continue to be told. If you’re interested in hearing about politics, how people lie to get ahead, and how the pious counteract the influence of the sinful, just immerse yourself in the Mahabharata

 

, which describes Krishna’s involvement in the famous feud between the Kauravas and Pandavas. If you like hearing about love stories, men and women getting together, condition yourself to learn about Shri Krishna and His eternal consort Shrimati Radharani

 

. Then hear about their dealings from a bona fide source. These pastimes, though very intimate and thus off limits to the neophyte, are documented in the Shrimad Bhagavatam for a reason. They give tremendous joy to those who have an anxious desire to hear about God and His activities.

If you like hearing about weddings, focus your mind on the famous ceremony held in Janaka’s kingdom, where Krishna in His form of Lord Rama

 

 lifted an extremely heavy bow belonging to Lord Shiva

 

 to win Janaka’s daughter’s hand in marriage. If you want to hear about the struggle for existence, the successful triumph over both physical and mental obstacles, travel back in time to when Shri Hanuman

 

, Rama’s most faithful servant, infiltrated the enemy territory of Lanka all by himself to find Rama’s missing wife, Sita Devi

 

.

These mental trips will be so worth it that you’ll eventually abandon your attachment to the temporary. The natural yearning towards service and stimulation of the mind doesn’t have to be artificially renounced. Rather, just by changing the subject matter, one can go from living a material existence to enjoying a spiritual life which is full of knowledge, bliss and eternality. The human being’s birthright is to love God, and by following the methods laid down by Krishna Himself, that destiny can become a reality.

In Closing:

Stories of celebrities in papers you’ll find,

Piques the curiosity of your mind.

From hearing about scorn, love and deceit,

Some pleasure in your mind you receive.

These tendencies don’t outwardly reject,

Focus on Krishna instead, change the subject.

With proper training hear of highest love,

Radha and Krishna always think of.

For bravery Hanuman, and Mahabharata politics,

This way guarantee of salvation when body you quit.

Extended synaptic development may explain our cognitive edge over other primates

Over the first few years of life, human cognition continues to develop, soaking up information and experiences from the environment and far surpassing the abilities of even our nearest primate relatives. In a study published online today in Genome Research, researchers have identified extended synaptic development in the human brain relative to other primates, a finding that sheds new light on the biology and evolution of human cognition.

"Why can we absorb environmental information during infancy and childhood and develop intellectual skills that chimpanzees cannot?" asks Dr. Philipp Khaitovich of the Chinese Academy of Sciences and the Max Planck Institute for Evolutionary Anthropology, senior author of the report. "What makes the human brain so special?"

Chimps diverged from the human lineage about 4-6 million years ago, a relatively short period of time by evolutionary standards. Yet the differences in specialized social and cultural cognitive skills between humans and chimps are striking, and much remains unknown about the biological basis.

To answer his questions, Khaitovich and an international team of researchers used microarray and RNA-sequencing technology to investigate changes in how genes are read, or expressed, during development of the postnatal brain in humans, chimps, and macaques, a more distantly related primate. And the timing of these changes may set human cognitive development apart from other primates. The group sampled the prefrontal cortex, a more recently evolved brain region associated with cognition, and the cerebellum, an ancient brain region related to motor control.

Khaitovich explained that evolutionary studies of the human brain often produce murky results, however this approach performed even better than expected, pointing them to a specific postnatal developmental process. "Among all developmental changes specific to the human brain, one process – synaptogenesis – clearly stood out." Khaitovich explained that synaptogenesis, the foundation of learning and memory in the developing brain, is characterized by the formation of synaptic connections, strengthening useful connections, and also elimination of useless connections.

The authors found that in humans, peak expression of synaptic genes in the prefrontal cortex is delayed until about age five, in contrast to chimps and macaques where this occurs in the first year of life. The authors noted that this human-specific change was only observed in the prefrontal cortex, and not in the cerebellum

"Our findings suggest that the human brain remains extremely plastic and susceptible to environmental input during the first five years of life," said Khaitovich. "Our study uncovers one of the important mechanisms potentially involved in evolution of human cognition."

More information: Liu X, Somel M,Tang L, Yan Z, Jiang X, Guo S, Yuan Y, He L, Oleksiak A, Zhang Y, Li N, Hu Y, Chen W, Qiu Z, Pääbo S, Khaitovich P. Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques. Genome Res doi: 10.1101/gr.127324.111

 

Provided by Cold Spring Harbor Laboratory

"Extended synaptic development may explain our cognitive edge over other primates." February 1st, 2012. http://medicalxpress.com/news/2012-02-synaptic-cognitive-edge-primates.html

 

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Robert Karl Stonjek

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.

---

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.”

__________

Courtesy St. Jude Children’s Research Hospital 

childhood brain tumors

cancer sequencing 

DNA organization