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For the last two decades, St. Jude has been at the forefront in identifying the underlying genetic abnormalities of childhood cancers. The last five years have marked steady progress—each piece of information uncovered, revealing new ways to fight cancer with more effective, less toxic treatments.
Cancer is triggered by harmful mutations in the genes of normal cells. These mutations can happen by accident, be caused by our environment or be inherited. By pinpointing the underlying genetic mutations that cause a normal cell to become cancerous, scientists hope to develop new medicines and optimize the use of current therapy. Although researchers worldwide have extensively studied cancer genetics, the vast number of genetic changes that lead to cancer have not yet been identified; as a result, the true genetic causes of most cancers remain elusive—especially in children.
St. Jude Children’s Research Hospital has been a leader in identifying the underlying genetic abnormalities of childhood cancers. Researchers have made key discoveries about leukemia, brain tumors and the eye cancer retinoblastoma, as well as how children’s DNA influence their response to certain medications.
In the past five years alone, St. Jude genetic research has had a worldwide impact on our knowledge of childhood cancer:
By identifying a specific pattern of gene expression linked to multiple-drug resistance of leukemic cells, St. Jude investigators provided crucial information into why standard therapies fail to cure some children with acute lymphoblastic leukemia (ALL).
St. Jude scientists determined that the patterns of gene expression in tumor samples show how brain tumors called ependymomas arise from rare stem cells in the nervous system and how targeted treatment of specific signal pathways can advance care of solid tumor patients.
Investigators worldwide were granted free access to a St. Jude tool for studying brain development. The Internet-based tool is one of the largest gene expression maps of an organ ever developed. The map may help scientists discover the genetic origins of brain cancers, which could speed development of novel drugs to treat them.
Scientists devised a new strategy to determine which biochemical signaling pathway triggers and sustains the brain tumor medulloblastoma by identifying key genes linked to that pathway. The technique could also be used to identify specific pathways in other types of cancer and could speed development of molecular-targeted therapies.
While studying the eye cancer retinoblastoma, St. Jude researchers determined how the disease is triggered by genetic loss of a protective mechanism that normally kills aberrant cells. Researchers then demonstrated in the laboratory a new, locally applied treatment for retinoblastoma that greatly reduced tumor size without causing the side effects common with standard chemotherapy.
St. Jude researchers gained a better look at the mutational landscape of ALL, discovering previously unsuspected mutations that contribute to ALL’s formation. The study demonstrated that it is possible to significantly speed the identification of the genetic lesions that are the underlying cause of not only ALL but also many other cancers, including those affecting adults.
In the largest study to analyze malignant transformation of gliomas in children, scientists found genetic abnormalities that might warn clinicians that a child’s low-grade tumor was likely to undergo malignant transformation.
Researchers from St. Jude discovered that individual children with ALL respond differently to the same drug treatment, and that the variances could be explained by differences in the children’s genetics. The insights gained in the study work toward the effort to individualize chemotherapy according to a patient’s genetics.
St. Jude investigators discovered evidence that a series of genetic mutations work together to initiate most cases of an aggressive and often-fatal form of ALL. The new study adds further support to a key concept in cancer genetics: Malignancies frequently require mutations in multiple genes in order to develop. These findings provide new avenues to pursue to gain a better understanding of these disease processes and to develop better therapies.
Which patients with ALL are most likely to relapse? Hospital investigators identified a gene abnormality that makes that prediction. This could lead to a genetic test to identify children at high risk of relapse; if the abnormality were identified in a patient, physicians could then assign more aggressive treatment in hopes of warding off relapse.
Scientists discovered in children with ALL scores of inherited genetic variations that clinicians might be able to use as guideposts for designing more effective chemotherapy for this cancer. The newly discovered genetic variations will likely give scientists a clearer understanding of why treatments fail in some patients with ALL, and how to predict early in treatment which children could be successfully treated with less aggressive treatment.
Building on previous genetic studies, St. Jude researchers pinpointed a new class of gene mutations that identify cases of ALL that have a high risk of relapse and death. The finding suggested specific drugs that could treat this high-risk leukemia subtype in children, using drugs that are already in clinical trials for similar blood diseases in adults.
After launching the most comprehensive analysisyet of the genome for childhood acute myeloid leukemia (AML), scientists found only a few abnormalities in the genetic blueprint. The finding suggests this cancer arises from just a handful of missteps and that the development of pediatric AML may require fewer genetic alterations than other cancers.
Hospital investigators published the first complete search of the human genome for inherited risk factors of pediatric ALL. Scientists identified variations in two genes that account for 37 percent of cases of this cancer, including a gene that may help predict drug response. The research—based on a complete survey of the human genome— offered the first proof that inheritance plays a role in childhood ALL.
St. Jude researchers championed efforts to understand the genetic mistakes that give rise to pediatric ALL, identifying a new chromosomal abnormality responsible for some cases. The research focused on the link between a deletion in a chromosome and a form of ALL that is particularly common in children with Down syndrome. The discovery has already resulted in new diagnostic tests and potential tools for tracking these patients’ response to treatment.
The most comprehensive analysis yet of the genetic imbalances at the heart of childhood brain tumors known as high-grade gliomas (HGGs) identified a cancer gene that is unusually active in some tumors and is now the focus of a St. Jude clinical trial.
St. Jude and Washington University School of Medicine embarked on a bold, three-year initiative to identify the mutations underlying childhood cancer. Scientists in the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project will sequence the entire genomes of both normal and cancer cells from 600 patients, comparing differences in the DNA to identify genetic mistakes that lead to cancer.
Despite this progress, cancer remains the leading cause of death by disease in U.S. children over 1 year of age. St. Jude scientists hope their current research will lead to breakthrough treatments and help save the lives of children worldwide.
“We are on the threshold of a revolution in our understanding of the origins of cancer,” says Dr. William E. Evans, St. Jude director and CEO.
The next five years promise to be even more exciting than the last.
Reprinted from Promise Summer 2010