Spontaneous and Irradiation-Induced Tumor Susceptibility in <i>Brca2</i> Germline Mutant Mice and Cooperative Effects with a <i>p53</i> Germline Mutation

McAllister, Kimberly A.; Houle, Christopher; Malphurs, Jason; Ward, Toni; Collins, N. Keith; Gersch, William; Wharey, Laura; Seely, John C.; Betz, Laura J.; Bennett, Lee; Wiseman, Roger W.; Davis, Barbara J.

doi:10.1080/01926230600611794

Cited by 15 publications

(12 citation statements)

References 48 publications

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“…Homozygous deletion of exon 27 in mice resulted in the development of various epithelial carcinomas, lymphomas and sarcomas however, no osteosarcomas and only one ovarian tumor were reported (McAllister et al, 2002). In contrast, further studies showed significantly more osteosarcomas in homozygous mice lacking exon 27 than in their heterozygous or wild-type counterparts, an effect that was greatly enhanced when the mice were also heterozygous for mutant p53 (McAllister et al, 2006). These authors point out that tumor spectrum in these models may be affected by the background strain genetics.…”

Section: Discussionmentioning

confidence: 97%

Characterizing a rat Brca2 knockout model

et al. 2006

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Evidence exists that BRCA2 carriers may have an elevated risk of breast, ovarian, colon, prostate, and pancreatic cancer. In general, carriers are defined as individuals with protein truncating mutations within the BRCA2 gene. Many Brca2 knockout lines have been produced and characterized in the mouse. We previously produced a rat Brca2 knockout strain in which there is a nonsense mutation in exon 11 between BRC repeats 2 and 3, and a truncated protein is produced. Interestingly, while such a mutation in homozygous mice would lead to limited survival of approximately 3 months, the Brca2 À/À rats are 100% viable and the vast majority live to over 1 year of age. Brca2 À/À rats show a phenotype of growth inhibition and sterility in both sexes. Aspermatogenesis in the Brca2 À/À rats is due to a failure of homologous chromosome synapsis. Long-term phenotypes include underdeveloped mammary glands, cataract formation and lifespan shortening due to the development of tumors and cancers in multiple organs. The establishment of the rat Brca2 knockout model provides a means to study the role of Brca2 in increasing cancer susceptibility and inducing a novel ocular phenotype not previously associated with this gene.

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Section: Discussionmentioning

confidence: 97%

Characterizing a rat Brca2 knockout model

et al. 2006

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“…Inactivation of p53 acts cooperatively with genetic alterations in other tumor suppressor or oncogenes to increase cancer risk (43). In this study, we showed that RAP80 −/− p53 −/− double knockout mice exhibited a greater decrease in tumor-free survival compared to p53 −/− single knockout mice indicating that the loss of RAP80 acts synergistically with the loss of p53 in promoting spontaneous lymphoma development.…”

Section: Discussionmentioning

confidence: 99%

RAP80 Is Critical in Maintaining Genomic Stability and Suppressing Tumor Development

et al. 2012

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The ubiquitin interaction motif (UIM)-containing protein RAP80 was recently found to play a key role in DNA damage response (DDR) signaling by facilitating the translocation of several DDR mediators, including BRCA1, to ionizing irradiation (IR)-induced foci (IRIF). In this study, we examine the effect of the loss of RAP80 on genomic stability and the susceptibility to cancer development in RAP80 null (RAP80−/−) mice. RAP80−/− mice are viable and did not exhibit any apparent developmental defects. Mouse embryonic fibroblasts (MEFs) derived from RAP80−/− mice underwent premature senescence compared to wild type (WT) MEFs, were more sensitive to IR, and exhibited a higher level of spontaneous and IR-induced genomic instability. RAP80−/− thymocytes were more sensitive to IR-induced cell death than WT thymocytes. RAP80−/− mice were more susceptible to spontaneous lymphoma development and the development of DMBA-induced mammary gland tumors. Moreover, the loss of RAP80 accelerated tumor formation in both p53−/− and p53+/− mice. Our data indicate that RAP80-deficiency promotes genomic instability and causes an increase in cancer risk consistent with the concept that RAP80 exhibits a tumor suppressor function.

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“…The strength and nature of each driver is distinct. For example, p53 and Notch can drive OS formation with complete penetrance, whereas Wif1 and Brca2 can induce OS in just a small percentage of mice [16, 17, 58, 70]. Furthermore, Apc , Ptch1 , and Prkar1a can only induce benign or low-grade malignant bone tumors, but not advanced OS [67, 68, 72].…”

Section: Understanding the Role Of Driver Gene Mutations In The Dementioning

confidence: 99%

Molecular genetics of osteosarcoma

Rickel

Fang

Tao

2017

Bone

207

179

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Osteosarcoma is the predominant form of bone cancer, affecting mostly adolescents. Recent progress made in molecular genetic studies of osteosarcoma has changed our view on the cause of the disease and ongoing therapeutic approaches for patients. As we draw closer to gaining more complete catalogues of candidate cancer driver genes in common forms of cancer, the landscape of somatic mutations in osteosarcoma is emerging from its first phase. In this review, we summarize recent whole genome and/or whole exome genomic studies, and then put these findings in the context of genetic hallmarks of somatic mutations and mutational processes in human osteosarcoma. One of the lessons learned here is that the extent of somatic mutations and complexity of the osteosarcoma genome are similar to that of common forms of adult cancer. Thus, a much higher number of samples than those currently obtained are needed to complete the catalogue of driver mutations in human osteosarcoma. In parallel, genetic studies in other species have revealed candidate driver genes and their roles in the genesis of osteosarcoma. This review also summarizes newly identified drivers in genetically engineered mouse models (GEMMs) and discusses our understanding of the impact of nature and number of drivers on tumor latency, subtypes, and metastatic potentials of osteosarcoma. It is becoming apparent that a synergistic team composed of three drivers (one ‘first driver’ and two ‘synergistic drivers’) may be required to generate an animal model that recapitulates aggressive osteosarcoma with a short latency. Finally, new cancer therapies are urgently needed to improve survival rate and quality of life for osteosarcoma patients. Several vulnerabilities in osteosarcoma are illustrated in this review to exemplify the opportunities for next generation molecularly targeted therapies. However, much work remains in order to complete our understanding of the somatic mutation basis of osteosarcoma, to develop reliable animal models of human disease, and to apply this information to guide new therapeutic approaches for reducing morbidity and mortality of this rare disease.

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Spontaneous and Irradiation-Induced Tumor Susceptibility in Brca2 Germline Mutant Mice and Cooperative Effects with a p53 Germline Mutation

Cited by 15 publications

References 48 publications

Characterizing a rat Brca2 knockout model

Characterizing a rat Brca2 knockout model

RAP80 Is Critical in Maintaining Genomic Stability and Suppressing Tumor Development

Molecular genetics of osteosarcoma

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