New insights into diagnosis and therapeutic options for proliferative hepatoblastoma
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ABSTRACT:
PROVIDER: PRJNA413799 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6154700_1.fastq.gz | Fastqsanger.gz | |||
| SRR6154700_2.fastq.gz | Fastqsanger.gz | |||
| SRR6154710_1.fastq.gz | Fastqsanger.gz | |||
| SRR6154710_2.fastq.gz | Fastqsanger.gz | |||
| SRR6154720_1.fastq.gz | Fastqsanger.gz |
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Project description:Surgery and cisplatin-based treatment of hepatoblastoma (HB) currently guarantee the survival of 70-80% of patients. However, some important challenges remain in diagnosing high risk tumors and identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of hepatoblastoma tumors have been described, namely C1 and C2; C2 being the subgroup with the poorest prognosis, a more advanced tumor stage and the worst overall survival rate. An associated 16-gene signature to discriminate the two tumoral subgroups was proposed but it has not been transferred into clinical routine. To address these issues we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A and C2B, identifiable by a concise four-gene signature: HSD17B6, ITGA6, TOP2A and VIM, with TOP2A being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by RT-qPCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in Fanconi Anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, an FDA-approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway associated double-strand DNA repair and significantly impedes HB growth in vivo. In conclusion, the highly proliferating C2A subtype is characterized by TOP2A gene up-regulation and FA pathway activation and HB therapeutic arsenal could include Bortezomib for the treatment of patients with the most aggressive tumors.
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