Susceptibility loci and chromosomal abnormalities in radiation induced hematopoietic neoplasms in mice.

Genetics of susceptibility to radiation-induced hematopoietic neoplasms and somatic chromosomal aberrations were analyzed in 305 backcross (CcS-17xCcS-2)xCcS-2 mice of two CcS/Dem recombinant congenic strains. Irradiated CcS-2 mice were previously shown to exhibit high frequency of myeloid neoplasms whereas irradiated CcS-17 mice were susceptible to T-cell lymphomas. Mice were exposed to four whole-body irradiation doses of 1.7 Gy at one week intervals, which resulted in 139 hematopoietic neoplasms. The hematopoietic neoplasms were classified according to the Bethesda proposals for classification of lymphoid and nonlymphoid hematopoietic neoplasms in mice. Genotyping of mice with 24 microsatellite markers and subsequent statistical analysis indicated linkage of the radiation induced T-lymphomas to two loci on chromosome 10 (D10Mit134) and chromosome 12 (D12Mit52). T-lymphoma susceptibility appeared to be linked to D10Mit134 in a sex dependent way. In contrast, the myeloid-granulocytic leukemias susceptibility is linked to combined effects of chromosome 5 (D5Mit179) and 16 (D16Mit34). Cytogenetic analysis was performed according to the standard G-bands procedure and confirmed using FISH method. We found non-random numerical and structural chromosomal changes in lymphoid neoplasms. Cytogenetic analysis indicated chromosomal aberrations presumably associated with lymphomagenesis, no specific cancer-related rearrangements were observed.

Opposite effects of modifiers of the ApcMin mutation in intestine and mammary gland.

Patterns of tumor susceptibility in different organs are widely divergent in mouse strains: one strain may be highly susceptible to tumors in one organ but resistant in another organ, whereas another strain may exhibit the opposite pattern (P. Demant, Semin. Cancer Biol., 3: 159-166, 1992). Therefore, susceptibility to tumors in different organs is assumed to be controlled by different sets of genes. On the other hand, many oncogenes and tumor suppressor genes are mutated in tumors from different organs, indicating that similar tumorigenic pathways operate in various tissues. To obtain insight into the interactions of susceptibility genes with one of such pathways, we compared tumorigenesis in intestine and mammary gland in recombinant congenic strains (RCSs) carrying the Apc(Min) mutation, affecting the Wnt pathway. The presence of Apc(Min) increased considerably the incidence of intestinal and mammary tumors. The individual RCSs differed in the number and latency of Apc(Min)-induced intestinal and mammary tumors and histological type of the latter. Unexpectedly, the strain distribution of susceptibility to the intestinal and mammary tumors in the Apc(Min)-bearing mice was opposite in the RCSs; the strains most susceptible for intestinal tumors were most resistant to mammary tumors and vice versa. This suggests that a set of genes controls the impact of the Apc(Min) mutation in both organs but with opposite effects. Elucidation of the basis of the observed strain differences in organ-specific Wnt pathway-mediated tumorigenesis will help to understand the interactions between germ-line encoded allelic differences in susceptibility genes and the spectrum of somatic mutations in tumor cells.