Highly aneuploid zebrafish malignant peripheral nerve sheath tumors have genetic alterations similar to human cancers

Abstract

Aneuploidy is a hallmark of human cancers, but most mouse cancer models lack the extensive aneuploidy seen in many human tumors. The zebrafish is becoming an increasingly popular model for studying cancer. Here we report that malignant peripheral nerve sheath tumors (MPNSTs) that arise in zebrafish as a result of mutations in either ribosomal protein (rp) genes or in p53 are highly aneuploid. Karyotyping reveals that these tumors frequently harbor near-triploid numbers of chromosomes, and they vary in chromosome number from cell to cell within a single tumor. Using array comparative genomic hybridization, we found that, as in human cancers, certain fish chromosomes are preferentially overrepresented, whereas others are underrepresented in many MPNSTs. In addition, we obtained evidence for recurrent subchromosomal amplifications and deletions that may contain genes involved in cancer initiation or progression. These focal amplifications encompassed several genes whose amplification is observed in human tumors, including met, cyclinD2, slc45a3, and cdk6. One focal amplification included fgf6a. Increasing fgf signaling via a mutation that overexpresses fgf8 accelerated the onset of MPNSTs in fish bearing a mutation in p53, suggesting that fgf6a itself may be a driver of MPNSTs. Our results suggest that the zebrafish is a useful model in which to study aneuploidy in human cancer and in which to identify candidate genes that may act as drivers in fish and potentially also in human tumors.array comparative genomic hybridization | fgf8 | met | Illumina | copy number alteration

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

“…Groundbreaking work by Amsterdam et al (88) has revealed that many genes encoding components of the ribosome act as haploinsufficient tumor suppressors in zebrafish. Follow-up studies have revealed that the MPNSTs that form from a loss of ribosomal genes exhibit a loss of p53 expression and are highly aneuploid (89)(90)(91). Recent work by Provost et al (92) showed that ribosomal gene rpl36 restrains Kras G12V -induced pancreatic cancer.…”

Zebrafish cancer: the state of the art and the path forward

“…Several mutations in p53 have now been identified, including M214K 17 , N168K 17 and I166T 67 . These zebrafish p53 mutants are susceptible to a number of heritable cancers, most prominently malignant peripheral nerve sheath tumours (MPNSTs), which are highly aneuploid 68 . In many respects, the p53-I166T mutation closely models Li–Fraumeni syndrome, and because p53 is inactivated or dysfunctional in most human cancers, this provides a genetic background on which to functionally test cooperation with candidate oncogenes.…”

Phylooncogenomics: Examining the cancer genome in the context of vertebrate evolution

“…Very recently, after strictly examining zebrafish malignant peripheral nerve sheath tumors (MPNST) that were induced by ribosomal protein ( rp ) and tp53 mutations, we revealed that these tumors are highly aneuploid, and that the aneuploid chromosomes show preferential presentations within a tumor and among fish tumors. For example, within a single fish tumor there is often preferential overrepresentation of chromosome 25 with simultaneous underrepresentation of chromosome 15 (Zhang et al, 2010). This finding is very similar with the aneuploidy chromosomes in human solid tumors (Wolman, 1986).…”