Genomic instability, as measured by microsatellite alterations, is not associated with liver tumor development in the genetically susceptible B6C3F1 mouse.
Certain human heritable forms of colon cancer have characteristically high frequencies of microsatellite alterations. These microsatellite changes are markers of genomic instability and the direct consequence of mutations in genes involved with DNA mismatch repair processes, which are in part responsible for maintaining the sequence integrity of the genome. Given that the B6C3F1 mouse is genetically predisposed to develop liver tumors we were interested in determining whether tumors derived in this strain of mouse may contain alterations in microsatellite sequences. The analysis of 48 tumors at 24 different microsatellite loci revealed that microsatellite alterations were detected in 12 of 48 tumors (25%). Although this frequency is relatively high, 11 of the 12 tumors exhibited only a single alteration and in 10 of those tumors this change was at the same microsatellite locus. Microsatellite alterations were also detected in the DNA isolated from 6 of 22 (27%) normal liver tissues with 4 of the 6 occurring at the same locus where the majority of changes were observed in the tumors. Based on these results, we conclude that the microsatellite alterations present in the mouse liver tumor tissue are most likely the result of spontaneous mutational events. Consequently, the genomic instability operational in a particular type of hereditary human colon cancer does not appear to be operational in the genetically predisposed B6C3F1 mouse liver. In addition, we demonstrated that the activation of the H-ras gene, which causes some forms of genetic instability in vitro, does not contribute to genetic instability within liver tumors as measured by microsatellite alterations.
Fox
T R
TR
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
McMillen
P J
PJ
Maronpot
R R
RR
Goldsworthy
T L
TL
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics* / Q000302:isolation & purification; D004198:Disease Susceptibility; D005260:Female; D011905:Genes, ras; D008099:Liver / Q000737:chemistry; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D051379:Mice; D018895:Microsatellite Repeats
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm