Search for chromosome instability in lymphocytes with germ-line mutations in DNA mismatch repair genes.
All colorectal cancer results from the accumulation of critical genetic alterations; however, the mechanisms of acquiring these mutations appear to be different in hereditary nonpolyposis colon cancer (HNPCC) and sporadic tumors with microsatellite instability compared with sporadic tumors with no microsatellite instability. To further explore the possible mechanisms of cancer predisposition in HNPCC, we studied chromosome breakage and induction of aneuploidy in the lymphoblastoid cell lines of four patients who were heterozygous for mutations in either hMSH2 or hMLH1--two components of the DNA mismatch repair complex. Cells were cultured under different stress systems, including exposure to bleomycin, mitomycin C, bromodeoxyuridine-induced sister chromatid exchange, and a DNA alkylator, N-methyl-N'-nitro-N-nitrosoguanidine. No significant differences were detected in the levels of major or minor chromosome breakage or aneuploidy compared with controls. These results suggest that a single "hit" to a DNA mismatch repair gene does not confer appreciable susceptibility to structural or numerical chromosomal alterations, which is consistent with previous observations that HNPCC-related cancers are more likely to be near diploid than are sporadic colon cancers.
Lindor
N M
NM
Department of Medical Genetics, Mayo Clinic, Mayo Foundation, Rochester, Minnesota, USA.
Jalal
S M
SM
VanDeWalker
T J
TJ
Cunningham
J M
JM
Dahl
R J
RJ
Thibodeau
S N
SN
D000782:Aneuploidy; D002461:Cell Line, Transformed; D002869:Chromosome Aberrations / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects; D016368:Frameshift Mutation; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D012854:Sister Chromatid Exchange / Q000187:drug effects
D008769:Methylnitronitrosoguanidine