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Identification of novel recurrent ETV6-IGH fusions in primary central nervous system lymphoma using high throughput RNA sequencing

ABSTRACT: We provide a novel gene fusion (ETV6-IgH) involving a truncation of ETV6 and leading to haploinsuffiency of ETV6 expression. ETV6-IgH is a new potential surrogate marker of PCNSL with favorable prognosis

ORGANISM(S): Homo sapiens

PROVIDER: GSE81816 | GEO | 2018/12/26

REPOSITORIES: GEO

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Identification of novel recurrent ETV6-IgH fusions in primary central nervous system lymphoma.

Project description:Background:Primary central nervous system lymphoma (PCNSL) represents a particular entity within non-Hodgkin lymphomas and is associated with poor outcome. The present study addresses the potential clinical relevance of chimeric transcripts in PCNSL discovered by using RNA sequencing (RNA-seq). Methods:Seventy-two immunocompetent and newly diagnosed PCNSL cases were included in the present study. Among them, 6 were analyzed by RNA-seq to detect new potential fusion transcripts. We confirmed the results in the remaining 66 PCNSL. The gene fusion was validated by fluorescence in situ hybridization (FISH) using formalin-fixed paraffin-embedded (FFPE) samples. We assessed the biological and clinical impact of one new gene fusion. Results:We identified a novel recurrent gene fusion, E26 transformation-specific translocation variant 6-immunoglobulin heavy chain (ETV6-IgH). Overall, ETV6-IgH was found in 13 out of 72 PCNSL (18%). No fusion conserved an intact functional domain of ETV6, and ETV6 was significantly underexpressed at gene level, suggesting an ETV6 haploinsufficiency mechanism. The presence of the gene fusion was also validated by FISH in FFPE samples. Finally, PCNSL samples harboring ETV6-IgH showed a better prognosis in multivariate analysis, P = 0.03, hazard ratio = 0.33, 95% CI = 0.12-0.88. The overall survival at 5 years was 69% for PCNSL harboring ETV6-IgH versus 29% for samples without this gene fusion. Conclusions:ETV6-IgH is a new potential surrogate marker of PCNSL with favorable prognosis with ETV6 haploinsufficiency as a possible mechanism. The potential clinical impact of ETV6-IgH should be validated in larger prospective studies.

| S-EPMC6280140 | biostudies-literature

Identification of ETV6 bound protein by affinity purification of ETV6-HA fusion protein in REH cells

Project description:To determine the protein partners of ETV6, we expressed ETV6 and HA-tagged ETV6 in Reh pre-B leukemic cells. Anti-HA magnetic beads were used for affinity purification of ETV6-HA (and ETV6 control) from the nuclear and cytoplasmic fraction. Following purification on-beads digest and LC-MS/MS experiments were performed at the Proteomics platform of the CHU de Quebec Research Center, Quebec, Canada.

2022-01-26 | PXD031001 | Pride

Genome-wide survey of adjacent gene rearrangements in breast cancer identifies triple-negative specific BCL2L14-ETV6 fusions

Project description:Purpose: We investigated the function of overexpressed BCL2L14-ETV6 fusion variants in triple-negative breast cancer using high-throughput mRNA sequencing (RNA-Seq) analysis in BT20 human basal-like breast cancer cell line. Methods: The BCL2L14-ETV6 fusion variants or wildtype ETV6 cDNA containing the full-length ORFs were subcloned into the lentiviral pLenti7.3 vector, and later transduced into the BT20 cell line. BT20 cells were cultured in EMEM (ATCC) with 10 % fetal bovine serum (Hyclone). Total RNA was extracted from cells in individual confluent 10 cm dish, using the standard procedure of Qiagen RNeasy kit. The NovaSeq 6000 library for DNA sequencing was prepared using TruSeq Stranded mRNA Library Prep Kit (Illumina) following the protocol provided by the manufacturer. The final libraries were normalized by quantification with LightCycler 480 II (Roche Applied Science, Indianapolis, IN, USA) and qualification with Bioanalyzer (Agilent, Palo Alto, CA, USA). The final loading concentration was adjusted to 10 pM following the NovaSeq 6000 loading protocol. The NovaSeq 6000 S2 Reagent Kit (Illumina) was used for paired-end reads (2×150 bp) sequencing reactions. Sequencing data was given as raw data with a Phred Q30 score of 80 or better. Results: Confirming the overexpression of BCL2L14-ETV6 fusion variants, the reads that match to partial of BCL2L14 and ETV6 mRNA transcripts were 32~256 fold higher in the stable BT20 cell lines expressing BCL2L14-ETV6 fusion, compared to the cells the express the vector control. We found some key genes in cell migration and invasion are up-regulated in these stable BT20 cells compared with the cells the express the vector control and the wildtype ETV6. Conclusions: BCL2L14-ETV6 fusions endow enhanced cell migration and invasion in breast cancer.

2020-03-28 | GSE120919 | GEO

Interstitial del(14)(q) involving IGH: a novel recurrent aberration in B-NHL

Project description:Using high-resolution array comparative genomic hybridization, we mapped del(14)(q) in a series of 23 B-cell leukemia/lymphoma cases. Interestingly, 14 cases with interstitial del(14)(q) showed involvement of IGH at 14q32.33. Whereas the proximal breakpoints of these deletions varied in 6 cases, they clustered in the 14q24.1/ZFP36L1 region in the 8 remaining cases. The latter del(14)(q24.1q32.33) covering approximately 36 Mb was further demonstrated in 12 additional patients by FISH. The majority of cases harboring this deletion were diagnosed as chronic lymphocytic leukemia (CLL) (75%), particularly atypical CLL, and were frequently associated with trisomy 12 (40%) and unmutated VH region (75%). Further analysis of the 14q32.33 breakpoints showed clustering in the constant region of IGH, proximal to the 5’ (Eµ) enhancer sequences. These findings therefore suggest that the del(14)(q24.1q32.33), and other analogous IGH-involving del(14)(q), might represent a novel aberration leading to activation of unknown oncogene(s) at 14q by its juxtaposition with regulatory elements of IGH. Extensive expression analysis via quantitative PCR and microarray profiling, however, failed to identify a gene uniformly upregulated in cases with del(14)(q24.1q32.33). Further investigations are needed to unravel the mechanism(s) and role of IGH-involving del(14)(q) in B-cell malignancies. Keywords: comparative genomic hybridization

2007-05-01 | GSE6713 | GEO

ETV6-NCOA2 expression profile in T/M mixed-phenotype acute leukemia [ETV6-NCOA2 human]

Project description:Exparession profiling of ETV6-NCOA2 at different stages of disease dEmpty vectorelopment: CD34 cord blood cells transduced with ETV6-NCOA2-GFP or with empty vector-GFP, CD34 cord blood cells transduced with ETV6-NCOA2-NGFR or ETV6-NCOA2-NGFR + NOTCH1-L1601PdP-GFP and transplanted in NSGS mice, and ETV6-NCOA2 patient derived xenografts.

2022-05-16 | GSE161702 | GEO

Examining the Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations

Project description:Oncofusions form when chromosomal translocations join two genes to create a protein with oncogenic properties. The oncogenic ETV6-NTRK3 (EN) gene fusion joins the sterile alpha domain of the ETV6 transcription factor with the tyrosine kinase domain of the neurotrophin-3 receptor NTRK3. Four EN variants with alternating break points have since been detected in a wide range of human cancers. To provide insight into EN oncogenesis, we employed a proximity labeling mass spectrometry approach to define the molecular context of the fusions. We identify 237 high-confidence interactors, which link EN fusions to several key signaling pathways, including ERBB, Insulin and JAK/STAT. We then assess the effects of EN variants on these pathways, and show that the pan NTRK inhibitor selitrectinib (LOXO-195) inhibits the oncogenic activity of EN2, the most common variant. This systems-level analysis of defines the molecular framework in which EN oncofusions operate to promote cancer.

2023-01-13 | MSV000091061 | MassIVE

ChIP-seq for RUNX1 and ETV6-RUNX1 in an induced pluripotent stem cell model of ETV6-RUNX1 pre-leukaemia

Project description:ETV6-RUNX1 is a first-hit mutation in childhood B cell precursor acute lymphoblastic leukaemia. ETV6-RUNX1 is a fusion protein which inherits the DNA-binding runt domain from RUNX1. Here we performed chromatin precipitation for native RUNX1 and ETV6-RUNX1 using RUNX1 antibodies and specifically for the ETV6-RUNX1 fusion using a V5-tag pull down.

2022-10-31 | E-MTAB-12208 | biostudies-arrayexpress

Expression data from primary central nervous system lymphoma (PCNSL) patients

Project description:This study aimed to define the genes associated with PCNSL patient survival. Expression profiling was performed on 34 PCNSLs. A gene classifier was developed. Thirty-four PCNSL patients were selected for RNA extraction and hybridization on Affymetrix microarrays.

2012-11-06 | E-GEOD-34771 | biostudies-arrayexpress

Pathway analysis of primary central nervous system lymphoma (PCNSL)

Project description:Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a “CNS signature.” Keywords: disease state analysis

2008-05-10 | GSE11392 | GEO

Genomic aberrations in primary central nervous system lymphoma (PCNSL)

Project description:Genomic aberrations in primary central nervous system lymphoma (PCNSL).

2010-11-13 | GSE25298 | GEO