BRCA2 and TP53 collaborate in tumorigenesis in zebrafish.
Germline mutations in the tumor suppressor genes BRCA2 and TP53 significantly influence human cancer risk, and cancers from humans who inherit one mutant allele for BRCA2 or TP53 often display loss of the wildtype allele. In addition, BRCA2-associated cancers often exhibit mutations in TP53. To dete...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3906131?pdf=render |
| _version_ | 1818975287904305152 |
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| author | Heather R Shive Robert R West Lisa J Embree Champa D Golden Dennis D Hickstein |
| author_facet | Heather R Shive Robert R West Lisa J Embree Champa D Golden Dennis D Hickstein |
| author_sort | Heather R Shive |
| collection | DOAJ |
| description | Germline mutations in the tumor suppressor genes BRCA2 and TP53 significantly influence human cancer risk, and cancers from humans who inherit one mutant allele for BRCA2 or TP53 often display loss of the wildtype allele. In addition, BRCA2-associated cancers often exhibit mutations in TP53. To determine the relationship between germline heterozygous mutation (haploinsufficiency) and somatic loss of heterozygosity (LOH) for BRCA2 and TP53 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 tp53(M214K) background had a high incidence of malignant tumors. The brca2(Q658X) mutation status determined both the incidence of LOH and the malignant tumor phenotype. LOH for tp53 occurred in the majority of malignant tumors from brca2 wildtype and heterozygous mutant zebrafish, and most of these were malignant peripheral nerve sheath tumors. Malignant tumors in zebrafish with heterozygous mutations in both brca2 and tp53 frequently displayed LOH for both genes. In contrast, LOH for tp53 was uncommon in malignant tumors from brca2 homozygotes, and these tumors were primarily undifferentiated sarcomas. Thus, carcinogenesis in zebrafish with combined mutations in tp53 and brca2 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 BRCA2 and TP53 mutations. |
| first_indexed | 2024-12-20T15:53:34Z |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T15:53:34Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-973eb28bbb9e404a8cf74a78890a03582022-12-21T19:34:34ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0191e8717710.1371/journal.pone.0087177BRCA2 and TP53 collaborate in tumorigenesis in zebrafish.Heather R ShiveRobert R WestLisa J EmbreeChampa D GoldenDennis D HicksteinGermline mutations in the tumor suppressor genes BRCA2 and TP53 significantly influence human cancer risk, and cancers from humans who inherit one mutant allele for BRCA2 or TP53 often display loss of the wildtype allele. In addition, BRCA2-associated cancers often exhibit mutations in TP53. To determine the relationship between germline heterozygous mutation (haploinsufficiency) and somatic loss of heterozygosity (LOH) for BRCA2 and TP53 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 tp53(M214K) background had a high incidence of malignant tumors. The brca2(Q658X) mutation status determined both the incidence of LOH and the malignant tumor phenotype. LOH for tp53 occurred in the majority of malignant tumors from brca2 wildtype and heterozygous mutant zebrafish, and most of these were malignant peripheral nerve sheath tumors. Malignant tumors in zebrafish with heterozygous mutations in both brca2 and tp53 frequently displayed LOH for both genes. In contrast, LOH for tp53 was uncommon in malignant tumors from brca2 homozygotes, and these tumors were primarily undifferentiated sarcomas. Thus, carcinogenesis in zebrafish with combined mutations in tp53 and brca2 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 BRCA2 and TP53 mutations.http://europepmc.org/articles/PMC3906131?pdf=render |
| spellingShingle | Heather R Shive Robert R West Lisa J Embree Champa D Golden Dennis D Hickstein BRCA2 and TP53 collaborate in tumorigenesis in zebrafish. PLoS ONE |
| title | BRCA2 and TP53 collaborate in tumorigenesis in zebrafish. |
| title_full | BRCA2 and TP53 collaborate in tumorigenesis in zebrafish. |
| title_fullStr | BRCA2 and TP53 collaborate in tumorigenesis in zebrafish. |
| title_full_unstemmed | BRCA2 and TP53 collaborate in tumorigenesis in zebrafish. |
| title_short | BRCA2 and TP53 collaborate in tumorigenesis in zebrafish. |
| title_sort | brca2 and tp53 collaborate in tumorigenesis in zebrafish |
| url | http://europepmc.org/articles/PMC3906131?pdf=render |
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