Loss of heterozygosity in spontaneous and X-ray-induced intestinal tumors arising in F1 hybrid min mice: evidence for sequential loss of APC(+) and Dpc4 in tumor development.
Min (multiple intestinal neoplasia) mice carry a mutant allele of the murine Apc (adenomatous polyposis coli) locus and are predisposed to intestinal adenoma formation in the intestinal tract. Early studies have shown complete loss of function of Apc by whole chromosome loss on the tumor-sensitive C57BL/6J genetic background and in AKR x B6 F1 hybrids. Gamma-radiation-induced chromosomal losses focus the critical region on wt Apc, but because of the limited number of polymorphic markers used, no other critical regions of loss on chromosome 18 were identified. Using intestinal tumors arising spontaneously and induced by X-rays in CBA/H x C57BL/6J F1 hybrid mice and high-resolution microsatellite loss of heterozygosity (LOH) techniques, we provide mapping data for wt Apc loss, which confirms and extends earlier observations. In addition, high-frequency loss events at the Dpc4 locus were found in both spontaneous and radiation-induced tumors. These data identified LOH of Dpc4 as a critical secondary event following complete functional loss of Apc. LOH across the Trp53 genomic region of chromosome 11 was not observed. No LOH was recorded for the Mom1 candidate gene Pla2g2a or for 9 out of 10 polymorphic markers from the Mom1 genomic region on murine chromosome 4. One marker mapping distal to Pla2g2a showed LOH in a small minority of spontaneous tumors. These data support the contention that Mom1 does not act as a classical tumor suppressor. Overall, our data indicates a significant role for Dpc4 mutation in intestinal tumor progression in the mouse and provides further evidence for the importance of interstitial chromosome losses in radiation tumorigenesis.
Haines
J
J
Radiation Effects Department, National Radiological Protection Board, Chilton, Oxfordshire, England.
Dunford
R
R
Moody
J
J
Ellender
M
M
Cox
R
R
Silver
A
A
D000818:Animals; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000528:radiation effects*; D005720:Gamma Rays; D017491:Genes, APC / Q000235:genetics / Q000528:radiation effects*; D016158:Genes, p53 / Q000235:genetics / Q000528:radiation effects; D007414:Intestinal Neoplasms / Q000235:genetics*; D008017:Life Expectancy; D019656:Loss of Heterozygosity / Q000235:genetics / Q000528:radiation effects*; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D018895:Microsatellite Repeats; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics / Q000528:radiation effects*; D014965:X-Rays
D004268:DNA-Binding Proteins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators