Solving the Puzzle

Pediatric Cancer Genome Project scientists learn more about the subtypes of a deadly childhood brain tumor.

Solving the puzzle

Seen from a few feet away, a puzzle’s image appears to be one seamless piece. But upon closer examination, that image actually consists of many pieces.

In 2010, research led by St. Jude Children’s Research Hospital investigators demonstrated for the first time that medulloblastoma — the most common malignant childhood brain tumor — is actually several different diseases, each arising from distinct cells destined to become different structures. The medulloblastoma puzzle, thought to be one disease, was discovered to have many parts, or subgroups.

Recently, our researchers discovered genetic mistakes in three of the four subtypes of medulloblastoma. These mistakes involve genes that are already the focus of drug development. The results mark progress toward more effective treatments for medulloblastoma and other cancers. The most significant gene alterations are linked to subtypes that currently have the best and worst prognosis.

“Medulloblastoma, which arises in the back of the brain in a region called the posterior fossa, is diagnosed in about 400 children and adolescents each year, and their outcome varies based on the subtype they have,” says Giles Robinson, MD, a St. Jude oncologist involved in the study.

Groups three and four are the most common — group three making up 25 to 30 percent, and group four making up 40 to 50 percent.

“About 60 to 70 percent of the kids we see in clinic at St. Jude have group three or group four tumors. Unfortunately, these are the subgroups that we know the least about,” Robinson says.

Examining the pieces

Understanding more about medulloblastoma subgroups could help doctors direct treatment more accurately, improving effectiveness and reducing side effects for patients.

“Currently, we call medulloblastoma all one disease,” Robinson says. “Patients come in, and they get surgery, radiation therapy and then chemotherapy — no matter what subtype of medulloblastoma they have. This study has major implications for the way we look at medulloblastoma, and the way we’ll potentially treat medulloblastoma.”

The study also uncovered totally unexpected genetic abnormalities within the disease subtypes that point scientists in new directions for improving treatments.

“In the WNT subgroup, which includes patients with the best outcome, we found a completely novel mutation that had never been described in medulloblastoma before,” says the project’s leader, Richard Gilbertson, MD, PhD, director of the St. Jude Comprehensive Cancer Center. “We also uncovered a big clue as to what might be driving subgroup three and four disease. The mutations in these tumors appear to work together to trick the cancer into ‘thinking’ it is still a stem cell. The tumor cells, therefore, behave just like early developing cells, and proliferate.” Drugs targeting some of the culprits identified in this study are already under development for other diseases. This gives the St. Jude team a head start on identifying potential treatments.

Glimpsing the bigger picture

The medulloblastoma research is part of the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project. Launched in 2010, this ambitious project is deciphering the complete normal and tumor genomes of 600 childhood cancer patients. The genome is the complete set of instructions needed for human life. It is carried in the DNA found in nearly every cell.

The study involved sequencing the complete normal and cancer genomes of 37 young patients with medulloblastoma, which translates to more than 222 billion letters of DNA code. This makes it the largest such effort to date for this disease.

Researchers uncovered a number of mutations in genes that orchestrate other genes through a process known as epigenetic regulation. They then checked tumors from an additional 56 patients and found the same alterations.

The findings add to mounting evidence from the Pediatric Cancer Genome Project that epigenetic changes play a pivotal role in fueling childhood cancer. Epigenetic mechanisms can serve as on-off switches, altering gene activity without changing the gene’s makeup. Such changes can lead to the unlimited cell growth of cancer.

“Medulloblastoma has been an exciting story in pediatrics because we’ve learned a lot throughout the years,” Gilbertson says. “The most exciting aspect of working at St. Jude is that it continually provides opportunities to better understand childhood cancers. When we complete one project, one set of experiments, and you think you’ve gotten to the end, there is another door that we can go through. It’s another door into a completely new world of alterations and understanding of the disease.

“The important thing to remember is that every time you go through one of those doors at St. Jude, it impacts patients’ lives.”

Reprinted from Promise Autumn 2012

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