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Mosaic Zebrafish Transgenesis for Functional Genomic Analysis of Candidate Cooperative Genes in Tumor Pathogenesis
Published on: March 31, 2015
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BRCA2 and TP53 collaborate in tumorigenesis in zebrafish
Heather R Shive1, Robert R West1, Lisa J Embree1
1Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Plos One
|February 4, 2014
Summary
Germline mutations in BRCA2 and TP53 influence cancer risk. Zebrafish studies show that loss of both gene copies is often required for tumor development, with specific mutations affecting tumor type.
Area of Science:
- Genetics
- Oncology
- Developmental Biology
Background:
- Germline mutations in BRCA2 and TP53 are linked to increased human cancer risk.
- Cancers in individuals with inherited BRCA2 or TP53 mutations often show loss of the functional gene copy.
- BRCA2-associated cancers frequently harbor TP53 mutations.
Purpose of the Study:
- To investigate the relationship between inherited heterozygous mutations (haploinsufficiency) and somatic loss of heterozygosity (LOH) for BRCA2 and TP53 in cancer development.
- To understand how these genetic alterations influence tumor formation and type.
Main Methods:
- Analysis of zebrafish with heritable mutations in BRCA2 and TP53.
- Histological examination of tumor-bearing zebrafish.
- Laser-capture microdissection of normal and neoplastic tissues for LOH analysis.
Main Results:
- Zebrafish with heterozygous tp53 mutations had a high incidence of malignant tumors.
- BRCA2 mutation status influenced LOH incidence and tumor phenotype.
- Loss of heterozygosity for tp53 was common in malignant tumors from brca2 wildtype and heterozygous mutants, often resulting in malignant peripheral nerve sheath tumors.
- Zebrafish with mutations in both genes frequently showed LOH for both BRCA2 and TP53.
- LOH for tp53 was rare in brca2 homozygotes, with tumors being primarily undifferentiated sarcomas.
Conclusions:
- Carcinogenesis involving combined BRCA2 and TP53 mutations typically requires biallelic inactivation or loss of at least one gene.
- The specific combination of inherited mutations impacts LOH development and the resulting tumor phenotype.
- Findings offer insights into cancer development linked to heritable BRCA2 and TP53 mutations.
