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Danio rerio

ABSTRACT: Highly Aneuploid Zebrafish Malignant Peripheral Nerve Sheath Tumors have Genetic Alterations Similar to Human Cancers

PROVIDER: PRJNA130823 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR065534.fastq.gz	Fastqsanger.gz
	SRR065535.fastq.gz	Fastqsanger.gz
	SRR065536.fastq.gz	Fastqsanger.gz
	SRR065537.fastq.gz	Fastqsanger.gz
	SRR065538.fastq.gz	Fastqsanger.gz

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Comparative oncogenomic analysis of copy number alterations in human and zebrafish tumors enables cancer driver discovery

Project description:The identification of cancer drivers is a major goal of current cancer research. Finding driver genes within large chromosomal events is especially challenging because such alterations encompass many genes. Previously, we demonstrated that zebrafish malignant peripheral nerve sheath tumors (MPNSTs) are highly aneuploid, much like human tumors. In this study, we examined 147 zebrafish MPNSTs by massively parallel sequencing and identified both large and focal copy number alterations (CNAs). Given the low degree of conserved synteny between fish and mammals, we reasoned that comparative analyses of CNAs from fish versus human MPNSTs would enable elimination of a large proportion of passenger mutations, especially on large CNAs. Accordingly, we found less than one third of the human CNA genes were co-gained or co-lost in zebrafish, dramatically narrowing the list of candidate cancer drivers for both focal and large CNAs. We conclude that zebrafish-human comparative analysis represents a powerful, and broadly applicable, tool to enrich for evolutionarily conserved cancer drivers. --- This filing comprises data related to GEO entry GSE23666 ("Highly Aneuploid Zebrafish Malignant Peripheral Nerve Sheath Tumors have Genetic Alterations Similar to Human Cancers"), representing a followup study. 147 pairs of zebrafish (Danio rerio) tumor (MPNST) and normal tail control samples

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Project description:The goal of this experiment was to compare the genes expressed in malignant peripheral nerve sheath tumors (MPNSTs) that arise in zebrafish as a result of homozygous mutation of the p53 gene or heterozygous mutation of several different ribosomal protein (rp) mutations. Since MPNSTs arise very rarely in wild type zebrafish, it seemed a possibility that p53 and rps may in fact be functioning in similar pathways. The tumors arising from the different mutations had been previously classified as similar by histology, thus the goal of the array experiments was to establish if any molecular signatures could be found that could delineate the p53 from the rp MPNSTs. Keywords: Zebrafish malignant peripheral nerve sheath tumors from different genetic backgrounds

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Project description:Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) that arise in persons with neurofibromatosis type 1 (NF1). Despite similar histological appearance, these neoplasms proceed along diverse evolutionary trajectories, with a subset progressing to a devastating form of sarcoma called malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathological features and CDKN2A copy number loss. While genomic studies have improved our understanding of key driver events promoting tumor progression, the transcriptional alterations that precede malignant transformation remain poorly understood. Here we resolve gene expression profiles in PNSTs across the neurofibroma-to-MPNST continuum in NF1 patients and genetically engineered mouse models, providing insight into nascent molecular features associated with neurofibroma evolution and transformation. These findings highlight the need for molecular diagnostic tools that augment conventional histopathological criteria to identify neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.

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