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Publicaciones Sobre Temas de Interés
CANCER GENOMA / BASE DE DATOS
The Pediatric Cancer Genome Project,
Nature Genetics,44:619–622,2012
Published online 29 May 2012
James R Downing, Richard K Wilson, Jinghui Zhang, Elaine R Mardis, Ching-Hon Pui, Li Ding, Timothy J Ley & William E Evans1
The St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project (PCGP) is participating in the international effort to identify somatic mutations that drive cancer. These cancer genome sequencing efforts will not only yield an unparalleled view of the altered signaling pathways in cancer but should also identify new targets against which novel therapeutics can be developed. Although these projects are still deep in the phase of generating primary DNA sequence data, important results are emerging and valuable community resources are being generated that should catalyze future cancer research. We describe here the rationale for conducting the PCGP, present some of the early results of this project and discuss the major lessons learned and how these will affect the application of genomic sequencing in the clinic.
Project design
In January 2010, St. Jude Children's Research Hospital and The Genome Institute at the Washington University announced the launch of the Pediatric Cancer Genome Project, a 3-year, $65-million privately funded initiative1. The stated goal of this effort was to sequence at 30-fold haploid coverage the whole genome of 600 pediatric tumors and matched non-tumor germline samples (1,200 total genomes) and to define the landscape of somatic mutations that underlie major subtypes of pediatric cancer. As leaders of this effort, it was our belief that a large pediatric-focused cancer sequencing effort was necessary to fully explore the genetic basis of the unique cancers seen in children. Thus, from the start, the PCGP was designed to complement the larger government-funded genomic efforts focused on adult cancers, including the US National Human Genome Research Institute (NHGRI)/National Cancer Institute (NCI) Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC) and the smaller NCI-funded pediatric project known as Therapeutically Applicable Research to Generate Effective Treatments (TARGET). With structural alterations, such as inter- and intrachromosomal rearrangements, being a common mechanism of mutagenesis in pediatric leukemias and solid tumors, we felt that a whole-genome sequencing (WGS) approach instead of exome or transcriptome sequencing would be required to accurately define the full spectrum of mutations in pediatric cancers. Our expectation was that the results from this project would catalyze research in pediatric malignancies and lead to improvements in our ability to diagnose, monitor and treat patients with targeted therapies aimed at the identified driver mutations.
We have recently completed the second year of the project. To date, the effort has not only yielded some remarkable surprises, but it has also generated one of the largest high-coverage whole-genome DNA sequence databases in cancer—a resource that will serve both cancer and non-cancer researchers for years to come. Here we highlight some of the important insights that have emerged from the PCGP, describe the resources we are making available to the scientific community and discuss the challenges that cancer genomics must overcome to gain a full understanding of the genetic lesions that underlie pediatric and adult cancers.
The spectrum of pediatric cancers sequenced
Despite the paucity of new drugs to treat childhood cancers during the past 20 years, the cure rates for these diseases have continuously improved: in developed countries, the overall cure rate for children with cancer now stands at ~80% (ref. 2). This success has been built on the use of cytotoxic chemotherapy and radiotherapies that are often associated with major side effects and can ultimately reduce the quality of life for survivors3. Although cure rates for childhood cancers are impressive relative to those for adult malignancies, cancer remains the leading cause of death by disease among children over 1 year of age in developed countries4. It is generally believed that new, less toxic curative treatments of childhood cancers should target the genetic alterations that drive these diseases. Elucidating the genetic abnormalities that underlie childhood cancers is therefore an essential step toward understanding the pathobiology of these diseases and using the information gained to develop more effective and less toxic treatments.
One could ask whether a pediatric cancer genome project is the best way to achieve the desired result or if sufficient understanding would emerge from the larger adult-focused projects. To those of us working in pediatric cancer research, the answer is obvious—children are not just small adults. The spectrum of cancers occurring in the pediatric population is markedly different from that seen in adults. For example, the major brain and solid tumors that arise in children, including medulloblastoma, neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma and Wilms tumor, are exceedingly rare in adults (Fig. 1a). Similarly, the specific genetic subtypes of acute lymphoblastic leukemia (ALL)—the most common malignancy in children—differ markedly between children and adults (Fig. 1b). This marked difference in the spectrum of cancers is not unexpected, in that many pediatric cancers are thought to arise within developing tissues that undergo substantial expansion during early organ formation, growth and maturation. The unique biology of these developing tissues suggests that the spectrum of mutations that lead to malignant transformation will also differ between pediatric and adult cancers. Thus, a focused project to characterize the landscape of mutations in pediatric cancers is necessary to achieve the goal of advancing cures for pediatric cancers.
Figure 1: Frequency of cancer diagnoses and leukemia subtypes in children and adults.
(a) The frequency of cancer types in children (left) and adults (right) on the basis of 2012 Surveillance, Epidemiology and End Results (SEER) data. Each chart is organized with cancers listed from the most common to the least common in a clockwise fashion.
(b) The frequency of T-cell lineage (blue text) and B-cell lineage (black text) subtypes of acute lymphoblastic leukemia (ALL) in children (left) and adults (right). Each chart is organized with ALL subtypes listed from the most common to the least common in a clockwise fashion. iAMP21, intrachromosomal amplification of chromosome 21.
So, what tumors should be sequenced first? Although statistical arguments suggest that 500 tumors of an individual subtype need to be sequenced to accurately identify all mutations occurring at a 5% or greater frequency, the relative rarity of pediatric cancers coupled with the heterogeneity of tumor subtypes makes this approach unfeasible in the short term. In fact, obtaining sufficient tumor samples has been a major limitation in the adult cancer genome sequencing projects. We therefore took the approach of sequencing the pediatric cancer subtypes for which outcome (cure) with current treatment is poor and/or where there is a conspicuous lack of knowledge regarding the genetic basis of the disease. To date, we have completed primary data acquisition and initial analyses for 260 pairs of pediatric cancer and matched non-tumor DNA from 15 specific tumor subtypes, as shown (Fig. 2). In the initial 3 years of our project, we plan on interrogating approximately an equal number of genomes from childhood leukemias, solid tumors and brain tumors.
Figure 2: Genetic landscape of 15 different types of pediatric cancers determined from whole-genome sequencing of 260 tumors and matching germline samples.close
The number of somatic mutations in each sample, including single-nucleotide variations (SNVs), insertion and/or deletion events (indels) and structural variations, is shown as the height in the three-dimensional graph. Only high-quality variations or…
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