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

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)...

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Bibliographic Details
Published in:PLoS genetics 2013-08, Vol.9 (8), p.e1003734-e1003734
Main Authors: Zhang, GuangJun, Hoersch, Sebastian, Amsterdam, Adam, Whittaker, Charles A, Beert, Eline, Catchen, Julian M, Farrington, Sarah, Postlethwait, John H, Legius, Eric, Hopkins, Nancy, Lees, Jacqueline A
Format: Article
Language:English
Subjects:
Aneuploidy
Animals
Cancer
Chromosome Aberrations
Chromosomes
Diagnosis
DNA Copy Number Variations - genetics
Gene Expression Regulation, Neoplastic
Genes, Neoplasm
Genetic aspects
Genetic code
Genome, Human
Genomics
Health aspects
High-Throughput Nucleotide Sequencing
Humans
Medical research
Neurilemmoma - genetics
Neurilemmoma - pathology
Oligonucleotide Array Sequence Analysis
Physiological aspects
Tumors
Zebra fish
Zebrafish
Zebrafish - genetics
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Summary: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. We established a list of orthologous genes between human and zebrafish, which includes approximately two-thirds of human protein-coding genes. For the subset of these genes found in human MPNST CNAs, only one quarter of their orthologues 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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1003734