title: Comparative oncogenomic analysis of copy number alterations in human and zebrafish tumors enables cancer driver discovery.
abstract: 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.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts, United States of America.
authors.forename: GuangJun
authors.initials: G
authors.lastname: Zhang
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hoersch
authors.forename: Adam
authors.initials: A
authors.lastname: Amsterdam
authors.forename: Charles A
authors.initials: CA
authors.lastname: Whittaker
authors.forename: Eline
authors.initials: E
authors.lastname: Beert
authors.forename: Julian M
authors.initials: JM
authors.lastname: Catchen
authors.forename: Sarah
authors.initials: S
authors.lastname: Farrington
authors.forename: John H
authors.initials: JH
authors.lastname: Postlethwait
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
authors.forename: Nancy
authors.initials: N
authors.lastname: Hopkins
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Lees
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D015894:Genome, Human; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009442:Neurilemmoma / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D015027:Zebrafish / Q000235:genetics