Cargando…
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...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906131/ https://www.ncbi.nlm.nih.gov/pubmed/24489863 http://dx.doi.org/10.1371/journal.pone.0087177 |
_version_ | 1782301444735500288 |
---|---|
author | Shive, Heather R. West, Robert R. Embree, Lisa J. Golden, Champa D. Hickstein, Dennis D. |
author_facet | Shive, Heather R. West, Robert R. Embree, Lisa J. Golden, Champa D. Hickstein, Dennis D. |
author_sort | Shive, Heather R. |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-3906131 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39061312014-01-31 brca2 and tp53 Collaborate in Tumorigenesis in Zebrafish Shive, Heather R. West, Robert R. Embree, Lisa J. Golden, Champa D. Hickstein, Dennis D. PLoS One Research Article 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. Public Library of Science 2014-01-29 /pmc/articles/PMC3906131/ /pubmed/24489863 http://dx.doi.org/10.1371/journal.pone.0087177 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Shive, Heather R. West, Robert R. Embree, Lisa J. Golden, Champa D. Hickstein, Dennis D. brca2 and tp53 Collaborate in Tumorigenesis in Zebrafish |
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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906131/ https://www.ncbi.nlm.nih.gov/pubmed/24489863 http://dx.doi.org/10.1371/journal.pone.0087177 |
work_keys_str_mv | AT shiveheatherr brca2andtp53collaborateintumorigenesisinzebrafish AT westrobertr brca2andtp53collaborateintumorigenesisinzebrafish AT embreelisaj brca2andtp53collaborateintumorigenesisinzebrafish AT goldenchampad brca2andtp53collaborateintumorigenesisinzebrafish AT hicksteindennisd brca2andtp53collaborateintumorigenesisinzebrafish |