<i>brca2</i> and <i>tp53</i> Collaborate in Tumorigenesis in Zebrafish

<div><p>Germline mutations in the tumor suppressor genes <i>BRCA2</i> and <i>TP53</i> significantly influence human cancer risk, and cancers from humans who inherit one mutant allele for <i>BRCA2</i> or <i>TP53</i> often display loss of the wildtype allele. In addition, <i>BRCA2</i>-associated cancers often exhibit mutations in <i>TP53</i>. To determine the relationship between germline heterozygous mutation (haploinsufficiency) and somatic loss of heterozygosity (LOH) for <i>BRCA2</i> and <i>TP53</i> in carcinogenesis, we analyzed zebrafish with heritable mutations in these two genes. Tumor-bearing zebrafish were examined by histology, and normal and neoplastic tissues were collected by laser-capture microdissection for LOH analyses. Zebrafish on a heterozygous <i>tp53^M214K</i> background had a high incidence of malignant tumors. The <i>brca2^Q658X</i> mutation status determined both the incidence of LOH and the malignant tumor phenotype. LOH for <i>tp53</i> occurred in the majority of malignant tumors from <i>brca2</i> wildtype and heterozygous mutant zebrafish, and most of these were malignant peripheral nerve sheath tumors. Malignant tumors in zebrafish with heterozygous mutations in both <i>brca2</i> and <i>tp53</i> frequently displayed LOH for both genes. In contrast, LOH for <i>tp53</i> was uncommon in malignant tumors from <i>brca2</i> homozygotes, and these tumors were primarily undifferentiated sarcomas. Thus, carcinogenesis in zebrafish with combined mutations in <i>tp53</i> and <i>brca2</i> typically requires biallelic mutation or loss of at least one of these genes, and the specific combination of inherited mutations influences the development of LOH and the tumor phenotype. These results provide insight into cancer development associated with heritable <i>BRCA2</i> and <i>TP53</i> mutations.</p>