Germ-line mutations in BRCA2 predispose to early-onset cancer. Homozygous mutant mouse, which has Brca2 truncated in exon 11 exhibit paradoxic occurrence of growth retardation and development of thymic lymphomas. However, due to its large embryonic lethality, cohort studies on the thymic lymphomas were not feasible. With the aid of Cre-loxP system, we demonstrate here that thymus-specific disruption of Brca2 allele without crossing it to p53-mutant background leads to the development of thymic lymphomas. Varying from 16 weeks to 66 weeks after birth, 25% of mice disrupted of Brca2 in the thymus died of thymic lymphomas, whereas previous report did not observe lymphomagenesis using similar Cre-loxP system. Future analysis of thymic lymphomas from these mice presented here will provide information on the cooperative mutations that are required for the BRCA2-associated pathogenesis of cancer.
Animals ; BRCA2 Protein/deficiency/*genetics ; CD4-CD8 Ratio ; Cell Separation ; Flow Cytometry ; Integrases/*genetics/immunology ; Lymphoma/*genetics/immunology/metabolism/pathology ; Mice ; Mice, Knockout ; Organ Specificity ; *Sequence Deletion ; T-Lymphocytes/enzymology/*immunology ; Thymus Gland/immunology/metabolism/pathology ; Thymus Neoplasms/*genetics/immunology/metabolism/pathology ; Tumor Suppressor Protein p53/deficiency/genetics/immunology

OBJECTIVETo investigate the possible relationship between defects in the FA/BRCA pathway of genomic stability and potential pathogenesis of T and B cell lymphoma.

METHODSNineteen cell lines derived from diverse subtypes of lymphoma for possible FA pathway defects were screened.

RESULTSNo defect in FANCD2 ubiquitination was observed. However, the FANCN protein was absent in cell lines HT and Sudhl4. This absence was correlated with enhanced MMC-induced G2 arrest, growth inhibition and high chromosomal breakage rate in both cell lines. In addition, in exon-5a of FANCN gene, a mutation of c.1769 C>T, p. A590V was found in cell line HT, but not in cell line Sudhl4.

CONCLUSIONThis mutation may be the reason causing the absence of the FANCN protein expression or making the protein unstable and losing its function.

Animals ; Antibiotics, Antineoplastic ; pharmacology ; BRCA2 Protein ; metabolism ; Base Sequence ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Chromosome Breakage ; drug effects ; Fanconi Anemia ; metabolism ; Fanconi Anemia Complementation Group D2 Protein ; metabolism ; Fanconi Anemia Complementation Group N Protein ; Gene Expression Regulation, Neoplastic ; Genomic Instability ; Humans ; Lymphoma ; genetics ; pathology ; Mitomycin ; pharmacology ; Molecular Sequence Data ; Mutation ; Nuclear Proteins ; chemistry ; deficiency ; genetics ; metabolism ; Protein Stability ; Sequence Analysis, DNA ; Signal Transduction ; Tumor Suppressor Proteins ; chemistry ; deficiency ; genetics ; metabolism