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Pioneering Project

St. Jude leads the way in genomic research in children's deadly diseases.

photograph courtesy St. Jude

Three years after launching a groundbreaking study‚Ä® involving human genetics, St. Jude Children’s Research Hospital reports significant discoveries in the complex realm of childhood cancers.

Since January 2010, scientists with the Pediatric Cancer Genome Project (PCGP), undertaken in partnership with Washington University School of Medicine in St. Louis, have been sequencing the normal and cancerous cells of 600 children who contributed tissue samples for the study. The human genetic code is written in the four-letter alphabet of the DNA molecule. By sequencing — or deciphering the order of — those letters in cancer cells and in normal cells, scientists are finding where “misspellings,” or mutations, occur. Pinpointing these mutations, which cause cells to morph into malignancies, is leading to better diagnostic tests and more effective treatments.

Over the past 15 years, various projects have studied genetic mutations that cause disease. However, mutations in pediatric cancers — still the leading cause of death by disease in children age 1 or older — have been largely overlooked in these studies. St. Jude researchers stress the need to examine childhood cancers separately from adult cancers because of distinctly different biology.

According to its website, to date the Pediatric Cancer Genome Project has yielded clues to the development of six deadly tumors or cancers — retinoblastoma; early T-cell precursor acute lymphoblastic leukemia; diffuse intrinsic pontine glioma; neuroblastoma; medulloblastoma; and acute megakaryoblastic leukemia. One finding showed that 78 percent of a certain category of brain-stem tumors carried changes in genes not previously linked to cancer. Another finding may explain why a child’s age at diagnosis for a nervous-system tumor can affect the outcome of the disease. Each discovery can lay groundwork for clinical care advances and new drug development.

For its role in the partnership, Washington University performs the genetic sequencing then transfers the data to St. Jude for validation and analysis. To expedite the process of sharing such enormous amounts of information, St. Jude created a detailed infrastructure to allow researchers to transport it at high speed and to store key files and algorithms.

Paramount to the project’s outcome is controlling for errors in sequencing to ensure that all potential variations and mutations are detected. Toward that end, St. Jude recruited computational biologist Dr. Jinghui Zhang, who, with her team of researchers, has developed a model for evaluating mutations and variations and to control for possible errors. Known as CREST, the model has been adopted globally.

Also going global is the DNA sequence data itself, which is now freely available to the worldwide scientific community — a fact that has prompted “strong and positive response,” according to Dr. James Downing, St. Jude’s scientific director leading the PCGP. More than 20 institutions have downloaded the complete data sets and are using  them for their research efforts, he says.

Moreover, the project’s Scientific Advisory Board, a group of leading scientists from across the U.S., were so impressed by the quantity and quality of of the data that the policy for data release set a new standard that the genomic scientific community must now follow.

Looking ahead, Downing says the genomic project will move in two major directions. First, “we’ll continue to explore the mutational landscape of pediatric cancer focusing on the large ‘desert’ regions of the genome, where the key regulatory control points for gene expression reside,” he explains. To date, no approach has been developed to accurately identify mutations in these regions. Study results will advance the field for both pediatric and adult cancers, as well as other genetic diseases.

Second, PCGP scientists will be developing the infrastructure and methodological approaches to apply this technology to the clinical management of patients with cancer — an effort that will pave new pathways in personalized medicine.

As part of the big picture, genomic studies play a small but vital role in finding cures for pediatric cancers. Says Downing, “Reaching a 100 percent cure will take a multidisciplinary approach involving all faculty and staff who work at St. Jude.”

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