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) are highly aneuploid, much like human tumors.

Many ribosomal protein mutations are associated with growth impairment and tumor predisposition in zebrafish.

We have characterized 28 zebrafish lines with heterozygous mutations in ribosomal protein (rp) genes, and found that 17 of these are prone to develop zebrafish malignant peripheral nerve sheath tumors (zMPNST). Heterozygotes from the vast majority of tumor-prone rp lines were found to be growth-impaired, though not all growth-impaired rp lines were tumor-prone. Significantly, however, the rp lines with the greatest incidence of zMPNSTs all displayed a growth impairment.

Identification of 315 genes essential for early zebrafish development.

We completed a large insertional mutagenesis screen in zebrafish to identify genes essential for embryonic and early larval development. We isolated 525 mutants, representing lesions in approximately 390 different genes, and we cloned the majority of these. Here we describe 315 mutants and the corresponding genes.

Many ribosomal protein genes are cancer genes in zebrafish.

We have generated several hundred lines of zebrafish (Danio rerio), each heterozygous for a recessive embryonic lethal mutation. Since many tumor suppressor genes are recessive lethals, we screened our colony for lines that display early mortality and/or gross evidence of tumors. We identified 12 lines with elevated cancer incidence.

Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate development.

To rapidly identify genes required for early vertebrate development, we are carrying out a large-scale, insertional mutagenesis screen in zebrafish, using mouse retroviral vectors as the mutagen. We will obtain mutations in 450 to 500 different genes--roughly 20% of the genes that can be mutated to produce a visible embryonic phenotype in this species--and will clone the majority of the mutated alleles. So far, we have isolated more than 500 insertional mutants.