Abstract
The potential role of fetal exposure in the increase of childhood cancers is still a matter of debate. Environmental and genetic factors, or combined effects of radiation with these factors need to be considered. We studied the effect of in utero exposure on lymphoma development using Mlh1-deficient mice, which are genetically prone to lymphoma. A germline mutation in MLH1, one of the DNA mismatch repair (MMR) genes associated with hereditary nonpolyposis colorectal cancer, causes childhood T- and B-cell leukemia, when homozygously defective. The tumors obtained from non-irradiated and in utero irradiated groups were diagnosed either thymic lymphoma or splenic lymphoma based on lymphoma-appearing anatomical site. According the cell-surface marker status, splenic lymphomas were further divided into two groups, T-cell origin (TCR+, CD4+ and CD8¬–) and B-cell origin (IgH+). Mutation analysis of Ikaros and Trp53 revealed that these genes were frequently mutated by one base insertion or deletion at mononucleotide repeat sequences, resulting in a frameshift mutation. Ikaros frameshift mutations were only found in thymic lymphomas, which were characterized TCR+, CD4+ and CD8+, indicating an immature T-cell. Trp53 frameshift mutation was found both T-cell and B-cell splenic lymphomas, the mutation was occurred about 50 % in each lymphoma with a heterozygous status. Radiation exposure increased point mutations in these genes in both thymic and splenic lymphomas. Interestingly, in utero exposure significantly shortened the latency of B-cell origin splenic lymphomas only, but did not affect those of thymic lymphomas and T-cell origin splenic lymphoma. Our data demonstrated that B-cell lymphoma development is accelerated by in utero exposure in Mlh1-deficient mice. Hence, in utero exposure should be paid more attention especially to persons with MMR gene-deficient background.
