DIPG Dad Juan Manuel Viu flew to the U.S. from Spain once again to meet with fellow DIPG Dad, John “Gungie” Rivera at The Cristian Rivera Foundation offices in New York last night. Dr. Jaume Mora, of Spain’s Hospital Sant Joan de Deu flew into Boston earlier in the week to speak with Dr. Mark Kieran of the Boston Children’s Hospital and Dana Farber Cancer Institute. The next stop on his trip included a meeting in New York with Dr. Mark Souweidane of Wiell Cornell and Memorial Sloan-Kettering Cancer Center. After speaking with both doctors about recent advancement in DIPG research plans, Dr. Mora met with John “Gungie” Rivera and Juan Manuel Viu at the CRF offices. From there, they enjoyed dinner at Babalu Restaurant in the Bronx to discuss upcoming collaboration to cure DIPG.
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 journalNature 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 theH3F3A 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.”
The study’s first authors are Gang Wu, Alberto Broniscer and Troy McEachron, all of St. Jude. The study’s other corresponding authors are Jinghui Zhang and James Downing, both of St. Jude. The other study authors are Charles Lu, Li Ding and Elaine Mardis, all of Washington University; and Barbara Paugh, Jared Becksfort, Chunxu Qu, Robert Huether, Matthew Parker, Junyuan Zhang, Amar Gajjar, Michael Dyer, Charles Mullighan, Richard Gilbertson and David Ellison, all of St. Jude.
The research was funded in part by the PCGP, including Kay Jewelers, a lead project sponsor; the National Institutes of Health, the Sydney Schlobohm Chair of Research from the National Brain Tumor Society; the Cure Starts Now Foundation, Smile for Sophie Forever Foundation, Tyler’s Treehouse Foundation, Musicians Against Childhood Cancer, the Noyes Brain Tumor Foundation and ALSAC.
St. Jude Children’s Research Hospital
Since opening 50 years ago, St. Jude Children’s Research Hospital has changed the way the world treats childhood cancer and other life-threatening diseases. No family ever pays St. Jude for the care their child receives and, for every child treated here, thousands more have been saved worldwide through St. Jude discoveries. The hospital has played a pivotal role in pushing U.S. pediatric cancer survival rates from 20 to 80 percent overall, and is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted to children. It is also a leader in the research and treatment of blood disorders and infectious diseases in children. St. Jude was founded by the late entertainer Danny Thomas, who believed that no child should die in the dawn of life. Join that mission by visiting www.stjude.org or following us on www.facebook.com/stjude and Twitter@StJudeResearch.
Washington University School of Medicine
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare. St. Jude Media Relations Contacts
When a person is diagnosed with a serious medical condition at any age it is devastating news for his or her friends and family. But when the parents of a four-year-old receive word that their child has an inoperable brain tumor, it’s earth shattering.
Unfortunately, that’s exactly what Farmingdale residents Erik and Cristina Bravin were told on July 21. Their daughter, Valentina, was diagnosed with Diffuse Intrinsic Pontine Glioma (DIPG), a tumor located in the middle of the brain stem, leaving the Bravin’s with a limited amount of treatment options to explore.
“It’s shocking,” Cristina said of the diagnosis. “There was a lot of anger and asking ‘Why us?” She added, “Nobody ever wants to hear anything negative about their child, let alone when they basically give her a death sentence.”
To help the Bravin’s with mounting medical and travel expenses, several fundraisers have been held in Valentina’s name including one at the Lynbrook VFW last November. Valentina’s aunt and uncle, Gina and Frank Orosz of Lynbrook, planned the event. It was attended by approximately 170 people and raised $26,000. There have also been fundraisers held in Valentina’s hometown of Farmingdale.
The Bravins didn’t waste any time to see what the possible routes of treatment were. “We basically went into search mode,” Cristina said. “We were researching every factor and treatment possible around the country and around the world.”
Their research led them to Houston, Texas where Valentina underwent 30 radiation treatments for six consecutive weeks at MB Anderson Cancer Center. The procedures started on Aug. 18 and ended Oct. 3.
Valentina, who turned five on New Year’s Eve, has been brave throughout her fight with DIPG according to her mom. “She’s a fighter,” Cristina said. “She doesn’t do things willingly, but when she does eventually comply with anything that doctors and nurses have to do she’s very tough.” Cristina said that the radiation treatment did shrink the tumor by 50 percent, but those results are usually temporary.
The Bravin’s were hoping Valentina would be accepted to a trial at Memorial Sloan-Kettering Cancer Center by Jan. 10, but according to Cristina the Food and Drug Administration (FDA) didn’t do them any favors.
“We were waiting for the FDA to approve this trial for several months,” Cristina said. “They finally approved it on Dec. 29 which didn’t leave much time for that cutoff date.” She said that Valentina missed the Jan. 10 cutoff by a few days because patients could not be admitted to the trial after 14 weeks since their last radiation treatment.
“It’s a life or death situation, but the FDA couldn’t care less,” she said.
After Valentina’s diagnosis, Cristina resigned from her job at Winthrop University Hospital and temporarily moved to Texas while her daughter underwent radiation treatment. Erik works in sales and has also taken a lot of time off in recent months.
Valentina, who likes ballet, ice skating and playing with Barbie dolls, will undergo an MRI on January 12 to check the status of her tumor. If the tumor is stable or has regressed, Cristina said Valentina may be considered for a new trial at the National Institutes of Health in Bethesda, MD.
Valentina’s grandfather started a foundation, Friends of Valentina, after the diagnosis. Cristina said the foundation is a medical trust fund to help cover expenses and to give Valentina special celebrations when she feels up to it.
If you would like to donate to or find out more information about Friends of Valentina, you can contact Gina at (516)384-9739 or Frank at (516)509-7862 or email@example.com.
Cristian Rivera Foundation Committee member, Jay Hernandez, was scoring goals on the west coast at the Lucile Packard Children’s Hospital at Stanford. He and fellow San Jose Earthquakes teammate, Bobby Burling, spent time with the patients there while teaming with MLS W.O.R.K.S. and the Starlight Children’s Foundation to introduce new gaming consoles being installed in the hospital. Jay proudly wore his Cristian Rivera Foundation wristband and referenced its founder, John “Gungie” Rivera, when telling about his inspiration for being involved with the children; “One thing I have experienced that maybe most guys haven’t is that I have a close friend of mine whose son passed away prematurely of childhood cancer, so any opportunity I get to contribute to do this kind of work hits close to home,” he said.
Jay and Bobby signed autographs and played games with the children, which was a wonderful distraction for one day that will surely leave a lasting impression on them. Thankfully, these children now have fun and challenging video games to play that will help them enjoy their childhood every day.