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

¹ National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27711, USA
² Experimental Pathology Laboratories, Inc., Research Triangle Park, North Carolina 27709, USA
³ Laboratory of Biosystems and Cancer, Genome Structure and Function Section, National Cancer Institute, Bethesda, Maryland 20892, USA
⁴ Constella Health Sciences, Durham, North Carolina 27708, USA
⁵ Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA
⁶ University of Wisconsin, Primate Research Center, Madison, Wisconsin 53706, USA
⁷ AstraZeneca R&D, Boston, Massachusetts 02451, USA

Correspondence: Address correspondence to: Kimberly Ann McAllister, National Institute of Environmental Health Sciences, NIH, MD EC-21, 79 Alexander Drive, Building 4401, Research Triangle Park, North Carolina 27709, USA; e-mail:mcallis2{at}niehs.nih.gov

Mutations in both p53 and BRCA2 are commonly seen together in human tumors suggesting that the loss of both genes enhances tumor development. To elucidate this interaction in an animal model, mice lacking the carboxy terminal domain of Brca2 were crossed with p53 heterozygous mice. Females from this intercross were then irradiated with an acute dose of 5 Gy ionizing radiation at 5 weeks of age and compared to nonirradiated controls. We found decreased survival and timing of tumor onsets, and significantly higher overall tumor incidences and prevalence of particular tumors, including stomach tumors and squamous cell carcinomas, associated with the homozygous loss of Brca2, independent of p53 status. The addition of a p53 mutation had a further impact on overall survival, incidence of osteosarcomas and stomach tumors, and tumor latency. The spectrum of tumors observed for this Brca2 germline mouse model suggest that it faithfully recapitulates some human disease phenotypes associated with BRCA2 loss. In addition, these findings include extensive in vivo data demonstrating that germline Brca2 and p53 mutations cooperatively affect animal survivals, tumor susceptibilities, and tumor onsets.

Key Words: Brca2 • p53 • irradiation • mice • Fanconi Anemia

Abbreviations: FA, Fanconi Anemia • Brca2^+/–, Brca2 heterozygous • Brca2^–/–, Brca2 homozygous mutant • Brca2^+/+, Brca2 wild-type • p53^+/+, p53 wild-type • p53^+/–, p53 heterozygous • p53^–/–, p53 homozygous mutant • Gy, Gray (unit of radiation)

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