Centers Search for Clues with Cancer Genome Sequencing

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As the field of genomic sequencing advances, 2 major medical centers recently announced efforts that are enabling them to find genetic mutations in specific cancers.

  • St. Jude Children's Research Hospital in Memphis, Tennessee, and Washington University School of Medicine in St. Louis, Missouri, have embarked on a joint collaboration to sequence the genomes of more than 600 patients with cancer, with the goal of understanding the genetic origins of a variety of pediatric cancers.

  • Researchers at the University of California, LosAngeles (UCLA) Jonsson Comprehensive Cancer Center performed the first complete genomic sequencing of a brain cancer cell line, which may ultimately lead to new ways to better monitor, diagnose, and treat glioblastomas.

Pediatric Genome Project

The St. Jude/Washington University effort, known as the Pediatric Genome Project, is estimated to cost $65 million (all from private donations) over 3 years. It is the largest whole-genome sequencing of pediatric cancers ever conducted andwill involvewhole genome sequencing of both normal and cancerous cell lines fromeach patient to determine specific DNA mutations that may be linked to cancer. The tumors studied will include childhood leukemias, brain tumors, and sarcomas.

“We think that, as a national resource in childhood cancers, we should step up and do this to help accelerate the entire field,” says James Downing, MD, scientific director and chair of the pathology department at St. Jude.

St. Jude has 1 of the largest childhood cancer tissue banks in the world, with more than 50,000 tumor, bone marrow, blood, and other biological samples. Meanwhile, the Genome Center at theWashington University School of Medicine is a world leader in high-speed,largescale sequencing of genomes, according to Dr.Downing.

Scientists'main goal is to lay out the landscape ofmutations occurring in the major, poor-outcome pediatric cancers—ultimately hoping to better understand the “driver” mutations that cause them.

“At the end of 3 years,we'll have a massive amount of data thatwill be publicly available with associated tools for others to analyze it,” Dr.Downing says.“We likely will have diagnostic markers and possible targets for which some drugs may already be available.” Ultimately, after the data are generated and overall costs of genomic sequencing decline, scientists and physicians will have to decide how best to turn the information into clinical practice, he notes.

St.Judewill provide tissue samples for the project,while Washington University researcherswill handle the sequencing. Teams from both institutions will conduct analyses and validation studies.The group also plans to coordinate an international meeting later this year to collaborate with investigators world wide who areworking on pediatricmalignancies. “We want to make sure no one is working on the same project, and we want to share our experience, analyses, and tools,” Dr. Downing says. “It's a race to learn, so we can cure these cancers.”

Key Points

  • St. Jude Children's Research Hospital andWashington University School ofMedicine have launched the Pediatric Genome Project, the largest whole-genome sequencing of pediatric cancers ever conducted.

  • The Pediatric Genome Project will last 3 years at an estimated cost of $65 million. It will involve sequencing the genomes of more than 600 cancer patients.

  • Upon completion of the project, St. Jude andWashington University scientists hope to have diagnostic markers and possible targets for drugs.

  • Researchers at UCLA's Jonsson Comprehensive Cancer Center performed the first complete genomic sequencing of a brain cell cancer line—a process that took less than a month and cost about $35,000.

  • Using the latest generation of sequencing technology, UCLA scientists hope to sequence many tens of thousands of individual cancers.

In previous research published during the last 2 years, Dr.Downing and St.Jude colleagues identified mutations in specific genes in cases of childhood acute lymphoblastic leukemia that have a high risk of relapse and death. One set of mutations—in a family of protein kinases called JAK—is a potential therapeutic target for a JAK kinase inhibitor. The Children's Oncology Group is organizing clinical trials to test this.

That research was part of the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, which attempts to use genomics to identify therapeutic targets in order to develop more effective treatments for childhood cancers. Unlike the Pediatric Cancer Genome Project, the TARGET studies have focused on only the few hundred genes already suspected of being involved in childhood cancers. Researchers from both projects will work collaboratively, Dr.Downing notes.“We've already made rapid progress using rather crude methods to find mutations—DNA microarrays with much less resolution than whole genome sequencing,” he adds.

Sequencing Glioblastomas

Meanwhile, at UCLA, scientists have used the latest sequencing technology on amuch-studied glioblastoma cell line,U87.1 The process took less than a month and cost about $35,000—compared with the many years, numerous researchers, and more than $1 billion it took to sequence the human genome.

“In a little over 10 years, the process of sequencing has become much more parallel and powerful,” notes Stanley Nelson, MD, professor of human genetics at UCLA and senior author of the study.“The process is much more efficient than gel-based technology,which has dominated the field.”

In fact,3 core technologies have led to a more cost-effective method of whole-genome sequencing, including Genome Sequencer FLX (Roche's 454 Life Sciences;Branford, Conn), Solexa (Illumina; San Diego, Calif), and SOLiD (sequencing by oligonucleotide ligation and detection; Life Technologies [formerly Invitrogen and Applied Biosystems]; Carlsbad, Calif). The latter enables sequencing of a whole genome for about $80,000,Dr.Nelson notes.By using SOLiD, Dr.Nelson and colleagues were able to generate the least expensive sequence to date of U87,which is used by thousands of laboratories worldwide.The sequencing will allow scientists whoare studying the cell line to reinterpret their findings and possibly point their research in new directions.

Virtually all potentially chromosomal translocations and genetic deletions and mutations that may contribute to this cancer were identified by the SOLiD sequencing process. Researchers took very long strands of genetic material from cancer cells and randomly cut them. Billions of different DNA fragments from the cancer were read simultaneously, and the genetic material was analyzed more than a billion times to ensure results.

A small subset of the DNA variation is likely driving these glioblastomas, and that determination process is ongoing, Dr.Nelson notes.He and his team created a website that provides the sequencing data for researchers who are conducting experiments related to U87:

Their next step is to generate more genetic evidence on specific genes that are relevant to various cancers.“We want to get the sequence of many tens of thousands of individual cancers,” Dr.Nelson says.“There are many individual cell lines that have been studied in labs, but we don't know the sequence of most cell lines that are commonly used in [laboratory] cultures.”

Although the UCLA researchers and others have proven that it is possible to handle and interpret such data,these scientists have not yet generated a sufficient amount of data to make clear interpretations of the relative importance of specific genes, Dr. Nelson adds. He believes that the medical world is not far away from performing routine whole genome sequencing in either healthy individuals or those with specific genetic mutations.Whether the sequencing will become affordable and accurate enough for physicians to use it in a clinical setting remains to be seen. Physicians will require tools that turn information into a format that will interpret these data for them. Dr. Nelson predicts that genomic sequencing costs may decline to about $2000 to $3000 by next year—a large decrease from $35,000.


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  2. Centers Search for Clues with Cancer Genome Sequencing