NATIONAL CANCER INSTITUTE
The genetic landscape of high-risk neuroblastoma
Nature Genetics
January 20, 2013
TARGET investigators used next generation whole genome, exome, and transcriptome sequencing to examine 240 cases of matched tumor and normal tissues from patients with metastatic high-risk neuroblastoma. Neuroblastoma is a type of cancer that arises in the developing sympathetic nervous system and is diagnosed primarily in infants and children. The study reported a low median frequency of exonic somatic mutations (0.60 mutations per megabase) and few genes overall that are recurrently mutated across the coding regions of these pediatric tumors. The frequently mutated genes detected include ALK, PTPN11, ATRX, MYCN, and NRAS with potentially pathogenic germline variants significantly enriched in ALK, CHEK2, PINK1 and BARD1. These results suggest that developing better treatment strategies for neuroblastoma patients will be challenging with a minimal number of targetable oncogenic drivers.
The molecular genetic makeup of acute lymphoblastic leukemia
Hematology Am Soc Hematol Educ Program
December 8, 2012
Recent efforts in high-resolution genomic profiling have helped characterize the genetic makeup of acute lymphoblastic leukemia (ALL). Dr. Charles Mullighan surveys the large collection of genetic alterations revealed from these studies in childhood ALL and explains how some of these alterations may be used to understand and predict treatment failure, as well as provide novel diagnostic markers and therapeutic targets. For example, patients harboring alterations commonly associated with poor treatment outcomes, such as IKZF1, may benefit from tyrosine kinase inhibitor therapy if kinase-activating alterations are also present. Investigators are currently defining the genetic landscape of ALL, and some key challenges ahead will be functionally validating the alterations driving ALL etiology and biology, as well as implementing practical clinical strategies derived from the genetic information.
Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from The Children’s Oncology Group TARGET Project
Blood
December 4, 2012
Ph-like acute lymphoblastic leukemia (ALL), a subtype of high-risk pediatric B-precursor ALL, has a gene expression profile (GEP) suggestive of activated tyrosine kinase signaling. TARGET researchers sequenced the tyrosine kinome and downstream signaling genes in 45 high-risk pediatric ALL cases with activated kinase signaling, including Ph-like ALL, to establish the incidence of tyrosine kinase mutations in this cohort. The study confirmed previously identified somatic mutations in JAK and FLT3, but did not find novel alterations in any additional tyrosine kinases or downstream genes. The mechanism of kinase signaling activation in this high-risk subgroup of pediatric ALL remains largely unknown.
Genome Study Points to Treatments for High-Risk Form of Childhood Leukemia
NCI Cancer Bulletin
September 4, 2012
NCI Cancer Bulletin features recently published findings from TARGET researchers using next generation sequencing and preclinical models to study high-risk acute lymphoblastic leukemia. Read the Bulletin article.
Genetic Alterations Activating Kinase and Cytokine Receptor Signaling in High-Risk Acute Lymphoblastic Leukemia
Cancer Cell
August 14, 2012
Transcriptome and whole genome sequencing of a high-risk subtype of B-progenitor acute lymphoblastic leukemia (B-ALL) have enabled TARGET researchers to identify novel gene rearrangements as well as activating mutations and deletions that may be targetable with current therapeutics. Activated kinase-like B-ALL does not harbor the BCR-ABL translocation, but it exhibits a very similar gene expression profile. The genetic alterations discovered in this study, which were validated by recurrence testing in a larger cohort, specifically affect cytokine receptors and regulators of kinase signaling. Moreover, several of the novel or rare alterations identified in this study induced cancerous phenotypes in cell lines and mouse xenograft models, and demonstrated sensitivity to tyrosine kinase inhibitors that are already used in the clinic. These results suggest that stratifying ALL patients may improve clinical outcomes through the use of therapies targeted to the specific genetic alteration.
TARGETing Childhood Cancer
Cancer Discovery
June 13, 2012
Read about recent progress from the TARGET initiative in an article in the American Association for Cancer Research journal, Cancer Discovery.
An NCI/NIH-sponsored TARGET session at AACR Annual Meeting 2012
The NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative: Using Large-Scale Genomics to Identify Novel Therapeutic Targets for Childhood Cancers
Time: Sunday, Apr 01, 2012, 3:30 PM - 5:30 PM
Description: This session will report on TARGET’s progress and lessons learned in the individual projects, how they further the mission of TARGET, as well as how the scientific community can access the data generated. The session will additionally summarize future directions and research opportunities for large-scale childhood cancer molecular characterization projects such as TARGET.
Presentations:
Introduction to TARGET – Malcolm A. Smith, M.D, Ph.D.
TARGET Project Highlights
High Risk Wilms Tumor – Elizabeth Perlman, M.D.
Osteosarcoma – Ching C. Lau, M.D., Ph.D
Acute Lymphoblastic Leukemia – Robert J. Arceci, M.D., Ph.D.
Neuroblastoma – Edward F. Attiyeh, M.D.
Acute Lymphoblastic Leukemia – Charles G. Mullighan, M.D., M.Sc.
Accessing TARGET Genomics Data –Jaime M. Guidry Auvil, Ph.D., and Tanja Davidsen, Ph.D.
Visit the AACR Webcast page to access slides and audio from this session. If you do not have an AACR webcast account, you must create one.
Cancer Genomics for Pediatric Cancers
October 11, 2011
Javed Khan, M.D., a molecular biologist at the National Cancer Institute (NCI), discusses the approach and implications of cancer genome programs such as TARGET in this video.
Key pathways are frequently mutated in high risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group
Blood
June 16, 2011
In the largest pediatric cancer genome sequencing effort reported to date, TARGET ALL researchers sequenced 120 candidate genes in 187 high-risk childhood B-precursor acute lymphoblastic leukemias (HR B-ALL). Integrated analysis combined validated somatic sequence mutations with results from genome-wide copy number alterations and gene expression profiles, and a high frequency of recurrent changes in key cancer signaling pathways was discovered. Further the frequency of mutations within the four major pathways varied greatly across genetic subtypes. These data highlight potential new therapeutic targets for in certain subsets of childhood ALL.
Ancestry and Pharmacogenomics of Relapse in Acute Lymphoblastic Leukemia
Nature Genetics
February 6, 2011
Epub ahead of print
In a letter published in Nature Genetics, pediatric researchers found that Native American ancestry is genetically linked with an increased risk of relapse in childhood acute lymphoblastic leukemia (ALL), the most common cancer in children. Various clinical studies have reported poorer survival among pediatric patients of self-reported African American or Hispanic ethnicity, as compared with either European American or Asian descent. Herein, the investigators use pharmacogenomics strategies to provide the first genome-wide association study to show a heritable genetic basis for ethnic disparities in cancer survival. Furthermore, the study demonstrates that the increased risk of relapse due to ancestry can be eliminated by incorporating an additional single phase of chemotherapy. These findings outline how genomics studies can lead to modifications in therapy that will result in better outcomes for cancer patients.
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