Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA236540 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Detection of a Recurrent DNAJB1-PRKACA Chimeric Transcript in Fibrolamellar Hepatocellular Carcinoma
| PRJNA236539 | ENA
Project description:The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma, a lethal disease lacking specific therapies. This study reports on the identification, characterization, and immunotherapeutic application of HLA-presented neoantigens specific for the DNAJB1-PRKACA fusion transcript in fibrolamellar hepatocellular carcinoma. DNAJB1-PRKACA-derived HLA class I and HLA class II ligands induce multifunctional cytotoxic CD8+ and T-helper 1 CD4+ T cells, and their cellular processing and presentation in DNAJB1-PRKACA expressing tumor cells is demonstrated by mass spectrometry-based immunopeptidome analysis. Single-cell RNA sequencing further identifies multiple T cell receptors from DNAJB1-PRKACA-specific T cells. Vaccination of a fibrolamellar hepatocellular carcinoma patient, suffering from recurrent short interval disease relapses, with DNAJB1-PRKACA-derived peptides under continued Poly (ADP-ribose) polymerase inhibitor therapy induces multifunctional CD4+ T cells, with an activated T-helper 1 phenotype and high T cell receptor clonality. Vaccine-induced DNAJB1-PRKACA-specific T cell responses persist over time and, in contrast to various previous treatments, are accompanied by durable relapse free survival of the patient for more than 21 months post vaccination. Our preclinical and clinical findings identify the DNAJB1-PRKACA protein as source for immunogenic neoepitopes and corresponding T cell receptors and provide efficacy in a single-patient study of T cell-based immunotherapy specifically targeting this oncogenic fusion.
2022-10-13 | PXD029882 | Pride
Project description:The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma (FL-HCC), a lethal disease lacking specific therapies. Here, we report on the identification, characterization and first immunotherapeutic application of HLA-presented neoantigens specific for the DNAJB1-PRKACA fusion transcript in FL-HCC. To characterize the T cell response against DNAJB1-PRKACA-derived HLA class I and HLA class II ligands, single cell RNA sequencing (scRNA-seq) and single cell TCR profiling from CD4+ and CD8+ T cells were performed using 10x Genomics single cell immune profiling.
2022-09-12 | GSE210337 | GEO
Project description:Most fibrolamellar carcinoma (FLC) is driven by a fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes of primary human hepatocytes; these recapitulated most changes observed in FLC. This is consistent with the observation that FLC is found in patients missing a regulatory subunit or with a ATP1B1::PRKACA fusion. Thus, the DNAJB1 domain is not required for FLC.
2024-05-17 | GSE237697 | GEO
Project description:Most fibrolamellar carcinoma (FLC) is driven by a fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). PKA holoenzyme activity is controlled through a regulatory protein (R) that both inhibits and localizes catalytic activity. An excess of regulatory subunits ensures PRKACA activity is normally inhibited. In FLC patient tumors driven by DNAJB1::PRKACA we find an increase in the ratio of catalytic to regulatory units by mass spectrometry, biochemistry and immunofluorescence, with increased kinase in the nucleus. Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes of primary human hepatocytes; these recapitulated most changes observed in FLC. This is consistent with the observation that FLC is found in patients missing a regulatory subunit or with a ATP1B1::PRKACA fusion. Thus, the DNAJB1 domain is not required for FLC. Instead, changes in PKA quantity and localization determine the FLC phenotype.
2024-05-17 | PXD043816 | Pride
Project description:Effects of fibrolamellar carcinoma-associated DNAJB1-PRKACA in HEK293T cells
| PRJNA679841 | ENA
Project description:Background & Aims: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer usually developed in non-cirrhotic livers of children and young adults with unknown etiology. Treatment is limited to surgical intervention. To date, molecular pathogenesis of FLC has been poorly characterized. Herein, we aim to provide an integrative genomic analysis from a large series of FLC patients. Methods: A clinically annotated cohort of 77 FLCs was analyzed through wholetranscriptome, SNP-array and whole-exome sequencing. Non-negative matrix factorization was performed for class discovery, and GSEA, NTP, IPA and immunohistochemistry for functional annotation. GISTIC algorithm identified chromosomal aberrations; Mutect and VarScan2, somatic mutations, and Random survival forest the prognostic signature, validated in an independent cohort. Results: Unsupervised gene expression clustering revealed 3 robust molecular classes: Proliferation-51%, enriched with liver cancer proliferation signatures and mTOR signaling activation, Inflammation-26%, with pro-inflammatory cytokines signatures, and Unannotated-23%, with non-liver-related cancer signatures. Neuroendocrine genes and cholangiocyte and hepatocyte histological markers were present in all classes. FLC showed few copy number variations, being the most frequent: focal amplification at 8q24.3(12.5%), and deletions at 19p13(28%) and 22q13.32(25%). DNAJB1-PRKACA fusion transcript was observed in 79% of cases. FLC tumors had 32 damaging mutations on average, affecting uncommon genes in liver neoplasms (BRCA2, U2AF1). An 8-gene prognostic signature predicted survival in FLC patients. Conclusions: FLC genomic analysis reveals a unique molecular portrait characterized by uncommon damaging mutations and chromosomal aberrations, and a highly prevalent fusion protein. Three molecular classes, including Proliferation and Inflammation, define the biological behavior. Prognostic signature will allow better patient stratification. Gene-expression profiles of fresh frozen human fibrolamellar hepatocellular carcinoma
2015-02-12 | E-GEOD-57726 | biostudies-arrayexpress
Project description:Background & Aims: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer usually developed in non-cirrhotic livers of children and young adults with unknown etiology. Treatment is limited to surgical intervention. To date, molecular pathogenesis of FLC has been poorly characterized. Herein, we aim to provide an integrative genomic analysis from a large series of FLC patients. Methods: A clinically annotated cohort of 77 FLCs was analyzed through whole transcriptome, SNP-array and whole-exome sequencing. Non-negative matrix factorization was performed for class discovery, and GSEA, NTP, IPA and immunohistochemistry for functional annotation. GISTIC algorithm identified chromosomal aberrations; Mutect and VarScan2, somatic mutations, and Random survival forest the prognostic signature, validated in an independent cohort. Results: Unsupervised gene expression clustering revealed 3 robust molecular classes: Proliferation-51%, enriched with liver cancer proliferation signatures and mTOR signaling activation, Inflammation-26%, with pro-inflammatory cytokines signatures, and Unannotated-23%, with non-liver-related cancer signatures. Neuroendocrine genes and cholangiocyte and hepatocyte histological markers were present in all classes. FLC showed few copy number variations, being the most frequent: focal amplification at 8q24.3(12.5%), and deletions at 19p13(28%) and 22q13.32(25%). DNAJB1-PRKACA fusion transcript was observed in 79% of cases. FLC tumors had 32 damaging mutations on average, affecting uncommon genes in liver neoplasms (BRCA2, U2AF1). An 8-gene prognostic signature predicted survival in FLC patients. Conclusions: FLC genomic analysis reveals a unique molecular portrait characterized by uncommon damaging mutations and chromosomal aberrations, and a highly prevalent fusion protein. Three molecular classes, including Proliferation and Inflammation, define the biological behavior. Prognostic signature will allow better patient stratification. Gene-expression profiles of formalin-fixed, paraffin-embedded human fibrolamellar hepatocellular carcinoma
2015-02-12 | E-GEOD-57725 | biostudies-arrayexpress
Project description:Fibrolamellar carcinoma (FLC) is a type of primary liver cancer that commonly arises in adolescents and young adults in a background of normal liver tissue and has an overall poor prognosis due to lack of effective chemotherapeutic agents. The DNAJB1-PRKACA gene fusion (DP) has been reported in the majority of FLC tumors, however its exact oncogenic mechanisms are unclear. Given the paucity of cellular models, in particular FLC tumor cell lines, we hypothesized that engineering the DP fusion gene in HEK293T cells will provide insight into the oncogenic mechanism of the fusion gene. We used CRISPR/Cas9 to engineer HEK293T clones expressing DP fusion gene (HEK-DP) and performed transcriptomic, proteomic, and mitochondrial studies to characterize this cellular model. Transcriptomic analysis of HEK-DP cells revealed a significant increase in LINC00473 expression similar to primary FLC samples. Proteomic analysis identified mitochondrial proteins as well as proteins in other subcellular compartments which interact with DP. HEK-DP cells demonstrated significant mitochondrial fission which suggests a role for DP in altering mitochondrial dynamics. Our results support the use of the HEK-DP cells as a novel model for elucidating the oncogenic mechanisms underlying DNAJB1-PRKACA-associated FLC pathogenesis and as a platform for high-throughput drug targeting of DNAJB1-PRKACA protein.
2022-04-05 | GSE161932 | GEO
Project description:Fibrolamellar carcinoma (FLC) is an aggressive liver cancer that predominantly afflicts adolescents and young adults. Patients with FLC are characterized by a heterozygous deletion on chromosome 19 that creates an oncogenic gene fusion, DNAJB1-PRKACA. The extracellular environment of FLC tumors is poorly characterized and may contribute to cancer progression, metastasis, and/or drug resistance. To bridge this knowledge gap, we propose to assess pathways relevant to proteoglycans, a major component of the extracellular matrix. We leveraged single-cell ATAC-seq to analyze the diversity of VCAN accessibility across different cell types.
2022-05-20 | GSE202315 | GEO