Date Published: May 11, 2004
Publisher: Public Library of Science
Author(s): Adam Amsterdam, Kirsten C Sadler, Kevin Lai, Sarah Farrington, Roderick T Bronson, Jacqueline A Lees, Nancy Hopkins
Abstract: 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. Fish from these lines develop malignant peripheral nerve sheath tumors, and in some cases also other tumor types, with moderate to very high frequencies. Surprisingly, 11 of the 12 lines were each heterozygous for a mutation in a different ribosomal protein (RP) gene, while one line was heterozygous for a mutation in a zebrafish paralog of the human and mouse tumor suppressor gene, neurofibromatosis type 2. Our findings suggest that many RP genes may act as haploinsufficient tumor suppressors in fish. Many RP genes might also be cancer genes in humans, where their role in tumorigenesis could easily have escaped detection up to now.
Partial Text: The zebrafish (Danio rerio) has long been used as a model organism for the identification of genes required for early vertebrate development (Kimmel 1989). There is reason to believe that the zebrafish can also be used in genetic screens to identify cancer genes. Zebrafish can live for 4–5 y (Gerhard et al. 2002), and like other fish species (Schmale et al. 1986; Wittbrodt et al. 1989), they develop tumors in a variety of tissues (Amatruda and Zon 2002; Smolowitz et al. 2002). They are also susceptible to chemical carcinogens and to well-known oncogenes, in a manner similar to the conventional mouse models (Beckwith et al. 2000; Spitsbergen et al. 2000a, 2000b; Langenau et al. 2003). Many of the spontaneous and chemically- or oncogene-induced tumor types are histologically similar to their mammalian counterparts (Amatruda and Zon 2002; Langenau et al. 2003).
In this study, we have found that heterozygous mutations in 11 different ribosomal protein genes predispose zebrafish to cancer, predominantly to zMPNSTs, but also to other rare tumor types. All of these mutations reduce RP gene expression, indicating that these 11 genes are not oncogenes. Moreover, in the tumors we examined, the wild-type allele appeared to be present and did not contain point mutations; thus these genes are not recessive tumor suppressors. Rather, our findings suggest that these 11 genes are haploinsufficient tumor suppressor genes; that is, reducing their activities by about a factor of two increases the likelihood of cancer. These findings raise two important, unanswered questions: first, how do these mutations lead to cancer, and second, do similar mutations cause cancer in humans?