Analysis of FOXO1 mutations in diffuse large B-cell lymphoma
March 4, 2013
Through RNA-seq and targeted exon sequencing analysis, investigators working in the CGCI program discovered FOXO1 frequently mutated in diffuse large B-cell lymphoma (DLBCL) cases. read more
FOXO1 is a nuclear transcription factor that regulates genes involved in B-cell differentiation and other important cellular processes. Most of the recurrent FOXO1 mutations clustered within two “hot spot” N-terminal regions, which are both predicted to disrupt interaction with negative regulator, 14-3-3. By expressing a few of the recurrent “hot spot” mutations in stable cell lines, the investigators demonstrated an absence of 14-3-3 binding and other related phenotypes. Clinical analysis revealed FOXO1 mutations are associated with lower overall survival rates, especially among DLBCL patients identified as low-risk by the revised International Prognostic Index (R-IPI). Together, these results suggest the importance of FOXO1 in DLBCL pathogenesis and the possibility of using FOXO1 mutations as a prognostic indicator in DLBCL patients.
The genetic landscape of high-risk neuroblastoma
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.
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.
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.
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.
Cancer Vulnerabilities Unveiled by Genomic Loss
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
Genetic Alterations Activating Kinase and Cytokine Receptor Signaling in High-Risk Acute Lymphoblastic Leukemia
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
TBL1XR1/TP63: a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma
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
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
Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma
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
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
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
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
Ancestry and Pharmacogenomics of Relapse in Acute Lymphoblastic Leukemia
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
Rewiring makes the difference
Molecular Systems Biology
January 18, 2011
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