Stay Connected

Scientific Publications

TARGET

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. read more

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.

CTD²

β-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and Tumorigenesis
Cell
December 21, 2012

Researchers participating in the CTD² initiative uncovered a novel role for the YAP1 transcriptional complex in β-catenin-dependent cell lines. These findings may have implications in colon and other cancers in which β-catenin contributes to tumor initiation and progression. read more

This work combined loss-of-function screening data mined from Project Achilles, a project partially supported by CTD², and gene expression/copy number analyses from the Cancer Cell Line Encyclopedia, with new β-catenin activity data across 85 cell lines. The integration of these data types allowed identification of 50 genes upon which β-catenin dependent cells preferentially rely for survival, including a number of genes related to the transcriptional regulator YAP1. Indeed, YAP1 was also required for tumor growth in a β-catenin dependent orthotopic colon tumor model. By further characterizing YAP1/β-catenin-mediated transformation, the group was able to find several factors linked to YAP1 that appear to be targetable with small molecules and might be suitable for use in future therapies.

TARGET

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 read more

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.

TARGET

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. read more

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.

CTD²

Cancer Vulnerabilities Unveiled by Genomic Loss
Cell
August 17, 2012

A group of researchers, including a member of the CTD² network, has identified 56 candidate genes upon which cancer cells are uniquely dependent for survival. read more

Integrated analysis of RNAi and copy number data across a panel of cancer cell lines revealed the CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss) genes, which include components of the spliceosome, ribosome and proteasome, as potential candidates for targeted cancer therapies. Partial loss of these genes may make tumor cells more sensitive than normal cells to gene suppression with targeted agents. In support of this theory, knockdown of the highest-ranked CYCLOPS candidate, the proteasome gene PSMC2, was shown to inhibit growth of ovarian tumor xenografts. The finding that passenger alterations in cancer cells can be therapeutically targeted, and not just the genes driving the cancer phenotype, experimentally validates an important concept in cancer research.

TARGET

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. read more

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.

CGCI

TBL1XR1/TP63: a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma
Blood
May 24, 2012

Using RNA sequencing (RNA-seq), Scott et al. discovered a novel recurrent gene fusion between TBL1XR1 and TP63 in diffuse large B-cell lymphoma (DLBCL). read more

Further analysis revealed the TBL1XR1/TP63 fusion was exclusive to DLBCL derived from germinal center B-cells. TBL1XR1 encodes a component of the NCoR/SMRT transcription repressor complex, and TP63 encodes a protein that is part of the TP53 family of transcription factors. These results demonstrate how RNA-seq is helping to reveal previously unidentified gene fusions in various cancers.

CTD²

Striking a Balance Between Feasible and Realistic Biological Models
Science Translational Medicine
October 5, 2011

The fusion of empirical science with large-scale computing platforms has allowed rapid advances in our ability to model physiological and pathophysiological processes in silico. read more

In this week's issue of Science Translational Medicine, Tran et al. present a simple framework for the quantitative modeling of oncogene addiction that provides mechanistic insights into tumor biology.

CGCI

Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma
Nature
July 27, 2011

In a recent Nature article, Morin et al. uncovered a novel role for chromatin modification in driving the progression of two non-Hodgkin lymphomas (NHLs), follicular lymphoma and diffuse large B-cell lymphoma. read more

Through DNA and RNA sequencing of 117 tumor samples and 10 assorted cell lines, the authors identified and validated 109 genes with multiple mutations in these B-cell NHLs. Of the 109 genes, several genes not previously linked to lymphoma demonstrated positive selection for mutation including two genes involved in histone modification, MLL2 and MEF2B. MLL2 emerged as a major tumor suppressor gene in both cancers, whereas, MEF2B appears restricted to lymphomas derived from germinal center B-cells. Their data provide potential therapeutic targets for NHL patients.

TARGET

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). read more

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.

CTD²

Towards systematic functional characterization of cancer genomes
Nature Reviews Genetics
July 13, 2011

Whole-genome approaches to identify genetic and epigenetic alterations in cancer genomes have begun to provide new insights into the range of molecular events that occurs in human tumours. read more

Although in some cases this knowledge immediately illuminates a path towards diagnostic or therapeutic implementation, the bewildering lists of mutations in each tumour make it clear that systematic functional approaches are also necessary to obtain a comprehensive molecular understanding of cancer. Here we review the current range of methods, assays and approaches for genome-scale interrogation of gene function in cancer. We also discuss the integration of functional-genomics approaches with the outputs from cancer genome sequencing efforts.

CTD²

Making sense of cancer genomic data
Genes & Development
April 8, 2011

High-throughput tools for nucleic acid characterization now provide the means to conduct comprehensive analyses of all somatic alterations in the cancer genomes. read more

Both large-scale and focused efforts have identified new targets of translational potential. The deluge of information that emerges from these genome-scale investigations has stimulated a parallel development of new analytical frameworks and tools. The complexity of somatic genomic alterations in cancer genomes also requires the development of robust methods for the interrogation of the function of genes identified by these genomics efforts. Here we provide an overview of the current state of cancer genomics, appraise the current portals and tools for accessing and analyzing cancer genomic data, and discuss emerging approaches to exploring the functions of somatically altered genes in cancer.

TARGET

Ancestry and Pharmacogenomics of Relapse in Acute Lymphoblastic Leukemia
Nature Genetics
February 6, 2011

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. read more

Using pharmacogenomic strategies, the investigators 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.

CTD²

Rewiring makes the difference
Molecular Systems Biology
January 18, 2011

OCG publications from:
2010
2009
2008
2006-2007

To sign-up to receive email updates on cancer genome news, program announcements, and funding opportunities, click here and provide the requested information.