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Homo sapiens

ABSTRACT: RNA-sequencing analysis of human fibrolamellar hepatocellular carcinoma and 4 maturational stages of the human hepatobiliary system

PROVIDER: PRJNA296091 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR2430370_1.fastq.gz	Fastqsanger.gz
	SRR2430370_2.fastq.gz	Fastqsanger.gz
	SRR2430380_1.fastq.gz	Fastqsanger.gz
	SRR2430380_2.fastq.gz	Fastqsanger.gz
	SRR2430371_1.fastq.gz	Fastqsanger.gz

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RNA-sequencing analysis of human fibrolamellar hepatocellular carcinoma and 4 maturational stages of the human hepatobiliary system

Project description:The etiology of fibrolamellar hepatocellular carcinoma (FL-HCC), a liver cancer occurring increasingly in children to young adults, is poorly understood. We performed high-throughput sequencing on mRNA isolated from a newly developed model of FL-HCC and 4 different maturational lineages of the hepatobiliary system. Our results indicate that the transcriptome of FL-HCC is most similar to that of biliary tree stem cells.

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The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma

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.

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Project description:Fibrolamellar hepatocellular carcinoma (FLC) is a rare type of primary liver cancer that often arises in children, adolescents and young adults. At the pathological level, FLC display pure morphology or can present with mixed morphology involving a conventional HCC component. Owing to the rarity of the disease, its genetic landscape is fully unknown. Pure FLC showed less chromosomic aberrations than mixed FLC and hepatocellular carcinoma arising in non-cirrhotic liverﾵ. Nevertheless; they displayed more gains in 16q23 and more LOH in 21q22. We also analyzed the mutational landscape of 8 FLC by whole-exome sequencing and showed mutations in the coagulation pathway.

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Project description:GENOMIC ANALYSIS OF FIBROLAMELLAR HEPATOCELLULAR CARCINOMA REVEALS A UNIQUE MOLECULAR PROFILE

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