Allelic loss analysis of γ-ray-induced mouse thymic lymphomas: two candidate tumor suppressor gene loci on chromosomes 12 and 16

Abstract

A total of 429 g-ray-induced thymic lymphomas were obtained from F 1 and backcross mice between BALB/c and MSM strains, about a half of which carried a p53-de®cient allele. A genome-wide allelic loss analysis has revealed two loci exhibiting frequent allelic losses but no allelic preference, one is localized within a 2.9 cM region between D12Mit53 and D12Mit279 loci on chromosome 12, and the other is near the D16Mit122/D16Mit162 loci on chromosome 16. The frequency of allelic loss in the D12Mit279 region is 62% and does not dier in tumors between the presence and absence of the p53-de®cient allele. In contrast, the loss frequency of D16Mit122 is raised by the existence of p53-de®cient allele: 62% for p63(7/+) and 13% for p53(+/+), suggesting cooperative function of the two losses. The D12Mit279 and D16Mit122 regions probably harbor dierent types of tumor suppressor gene that play key roles in lymphoma development.

Allelic loss mapping and physical delineation of a region harboring a putative thymic lymphoma suppressor gene on mouse chromosome 12

“…The 245 informative thymic lymphomas used in this study were previously obtained from F 1 hybrid and N 2 backcross mice between BALB/c and MSM carrying a p53-de®cient allele (Matsumoto et al, 1998). In this study additional 116 lymphomas were generated from the F 1 hybrid mice, about a half of which carried a p53-de®cient allele, by fractionated doses of g-ray irradiation, 2.5 Gy four times at a week interval, when the mice were at age of 4 weeks.…”

“…The D12Mit279 locus in the vicinity of Tlsr4 showed allelic loss at a frequency of as high as 62% and the frequency was not a ected by the presence or absence of a p53-de®cient allele in irradiated mice (Matsumoto et al, 1998). Interestingly, the Tlsr4 interval on mouse chromosome 12 is homologous to human chromosome 14q32 ± 33 where frequent allelic losses have been found in a variety of tumors: ovarian tumors (Bandera, 1997), colorectal carcinomas (Young et al, 1993), neuroblastomas (Suzuki et al, 1989) and invasive bladder cancer (Chang et al, 1995).…”

“…Santos et al (1996Santos et al ( , 1998 examined murine thymic lymphomas and suggested the existence of a putative tumor suppressor gene in a 0.6 cM region on chromosome 4. We also performed such analysis for murine thymic lymphomas that were induced by girradiation in F 1 hybrid mice and N 2 backcross mice between BALB/c and MSM strains (Matsumoto et al, 1998). A genome-wide analysis identi®ed two chromosomal regions exhibiting frequent allelic loss.…”

Genetic loci controlling susceptibility to γ-ray-induced thymic lymphoma

“…The distribution of the two groups di ered for all three loci. The susceptibilitygiving alleles were located in the vicinity of D2Mit15 Genotyping with microsatellite markers was carried out as previously described (Matsumoto et al, 1998). (c) Distributions in two di erent genotype groups, one (S/S) receiving two susceptibility alleles and the other (R/R) two resistance alleles.…”

“…There are many di erent inbred mouse strains that show variation in cancer susceptibility. For instance, BALB/ c is a susceptible strain to the development of thymic lymphoma after exposure to g-ray radiation (Meruelo et al, 1981;Okumoto et al, 1990) while MSM, an inbred strain derived from Japanese wild mice, Mus musculus molossinus, shows resistance (Matsumoto et al, 1998). Crossing of the sensitive and resistant strains may provide valuable information about the number of genes involved, their approximate locations, and the dominant or recessive nature of the susceptibility.…”