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BALB/c mice are sensitive to radiation-induced lymphomagenesis, while STS mice are resistant. Using 219 [(BALB/c x STS)F(1) x BALB/c] (N2C) and 197 [(BALB/c x STS)F(1) x STS] (N2S) animals, we performed a genome-wide search for loci controlling susceptibility to lymphomagenesis induced by radiation. Association of markers with the survival of animals was analyzed by the log rank test. For N2C mice, a significant correlation was detected, with four markers on the proximal to mid portion of chromosome 4: D4Mit302 and D4Mit255, P = 0.0075; D4Mit17, P = 0.034; and D4Mit86, P = 0.048. On the other hand, no significant linkage was detected in N2S mice. We analyzed BALB/c mice congenic for the STS allele in different regions of chromosome 4 and identified a locus with a conspicuous effect on survival located within a 7-Mb region between D4Mit302 and D4Mit144, where BALB/c mice harbor hypomorphic variant alleles of the tumor suppressor gene Cdkn2a, which encodes the cyclin-dependent kinase inhibitor protein p16INK4a. Using pooled F(2) intercrosses between the BALB/c and congenic lines carrying the STS allele near D4Mit17, but not in the range from D4Mit302 to D4Mit144, we assigned the second locus to an 11.4-Mb region in the vicinity of D4Mit17. Although Cdkn2a is a likely candidate for the locus controlling susceptibility to lymphomagenesis on chromosome 4, a novel tumor susceptibility gene different from Cdkn2a exists near the primary locus.

Mutations of Fas (CD95/Apo-1) gene have been reported in various malignancies and therefore the Fas gene has been considered to be a tumor suppressor gene. To examine an involvement of Fas gene as a tumor suppressor gene in radiation lymphomagenesis, we examined the loss of heterozygosity (LOH) in lymphomas from (MSM/Ms x MRL-MpJ/Fas (lpr)) F(1) and (BALB/cHeA x MRL-MpJ/Fas (lpr)) F(1) hybrid mice. Lymphoma development by X-irradiation was efficiently observed in both F(1) hybrids. Frequent LOH was found on chromosomes 12 and 4 in the tumors from both F(1) mice, but no allelic loss on chromosome 19 containing Fas locus was found, and no wild-type allele of the Fas gene was lost in 51 lymphomas. Therefore, the putative tumor-suppressor gene regions responsible for lymphomagenesis might not considerably differ due to the Fas gene status.

Regions of allelic loss on chromosomes in many tumors of human and some experimental animals are generally considered to harbor tumor-suppressor genes involved in tumorigenesis. Allelotype analyses have greatly improved our understanding of the molecular mechanism of radiation lymphomagenesis. Previously, we and others found frequent loss of heterozygosity (LOH) on chromosomes 4, 11, 12, 16 and 19 in radiation-induced lymphomas from several F1 hybrid mice. To examine possible contributions of individual tumor-suppressor genes to tumorigenesis in p53 heterozygous deficiency, we investigated the genome-wide distribution and status of LOH in radiation-induced lymphomas from F1 mice with different p53 status. In this study, we found frequent LOH (more than 20%) on chromosomes 4 and 12 and on chromosomes 11, 12, 16 and 19 in radiation-induced lymphomas from (STS/A X MSM/Ms)F1 mice and (STS/A X MSM/Ms)F1-p53KO/+ mice, respectively. Low incidences of LOH (10-20%) were also observed on chromosomes 11 in mice with wild-type p53, and chromosomes 1, 2, 9, 17 and X in p53 heterozygous-deficient mice. The frequency of LOH on chromosomes 9 and 11 increased in the (STS/A X MSM/Ms)F1-p53KO/+ mice. Preferential losses of the STS-derived allele on chromosome 9 and wild-type p53 allele on chromosome 11 were also found in the p53 heterozygous-deficient mice. Thus, the putative tumor-suppressor gene regions responsible for lymphomaganesis might considerably differ due to the p53 status.

The loss of heterozygosity (LOH) has been reported in numerous neoplasms in both human and animals, and has often been observed in chromosomal regions, which contain tumor-suppressor genes. We previously found frequent LOH on chromosomes 4, 12 and 19 in radiation-induced lymphomas from (BALB/cHeA x STS/A)F1 hybrid mice by allelotype analysis at polymorphic microsatellite loci. In this study, to elucidate the nature of allelic losses, we refined the loss regions on chromosomes 4, 12 and 19 of the tumors from the F1 mice and then analyzed them cytogenetically. The results represent evidence of a wide range of allelic losses owing to mitotic recombination on chromosomes 4 and 19 in the tumors, possibly reflecting functional losses of putative tumor-suppressor genes. It is suggested that the generation of these large homozygous chromosomal segments probably containing the affected genes is one of the genetic alterations responsible for tumorigenesis.