New method helps St. Jude scientists unlock childhood cancer mystery - East Valley Tribune: Nation / World

New method helps St. Jude scientists unlock childhood cancer mystery

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Posted: Tuesday, June 14, 2011 8:15 am

MEMPHIS, Tenn. - Sifting through 100 gigabytes of data relating to billions of pieces of genetic information, researcher Jinghui Zhang needed a new tool to better pinpoint the relatively small number of mutations that lead to childhood cancer.

In a computing method called CREST, she found it.

Developed by Zhang, "Clipping Reveals Structure," as the method is formally known, is offering scientists at St. Jude Children's Research Hospital a more accurate and efficient way to differentiate the mutations and genetic missteps that are associated with tumors from those that are not.

"There is a lot of data to analyze," said Zhang, an associate member of St. Jude's department of computational biology. "It's not going to be millions of mutations (that lead to cancer); it's going to be a few key lesions."

Zhang was the senior author of a study on the new computational method published Sunday in the advance online edition of the scientific journal Nature Methods. It reported that with CREST scientists identified 89 new structural differences in the cancer genomes of five St. Jude patients with an aggressive subtype of acute lymphoblastic leukemia, and found 50 new variations in melanoma cells.

The development of the computing tool came as part of the three-year, $65 million Pediatric Cancer Genome Project launched in January 2010 by St. Jude and Washington University School of Medicine in St. Louis.

"I think it's the first tangible output from the project," Dr. Jim Downing, scientific director at St. Jude, said of CREST.

The goal of the genome project is to crack the code of childhood cancer by identifying the genetic changes that give rise to tumors. That understanding, researchers say, should open the way for revolutionary improvements in the treatment of cancer, which, despite the dramatic improvements in survival rates at St. Jude and elsewhere, remains the No. 1 cause of death by disease for American children and adolescents.

In the three-year project, scientists are sequencing and comparing the complete normal genomes and cancer genomes from 600 St. Jude patients fighting some of the most aggressive forms of the disease.

A human genome is the blueprint for how a person grows and develops -- the full complement of genetic material, mainly the set of chromosomes and the genes they carry, inherited from parents.

Cancer can arise from mutations within any of the 3 billion base pairs of DNA distributed over 23 pairs of chromosomes. The mutations activate certain genes that alter a cell's biochemistry and remove regulatory controls, thereby triggering unchecked growth.

From the beginning, St. Jude researchers realized the biggest challenge in the project involved finding the dozen or so mutations that drive the development and growth of tumors.

To do it, they're using next-generation sequencing technology to break the long, double-stranded DNA molecule into millions of smaller fragments, which then are copied, and, using a reference human genome as a template, reassembled.

It's a painstaking process that Downing likens to tearing the pages out of a book, ripping each page into tiny pieces, and then putting the whole book back together again.

Previous computing algorithms yielded mostly false-positives and outright "garbage," Downing said.

CREST highlights the DNA segments that fail to align properly to the reference genome during the reassembly process, indicating a "tumor-specific event," Zhang said.

The new process is accurate more than 80 percent of the time, according to results in St. Jude's validation lab.

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