MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis.
Accelerated intestinal tumorigenesis is probable in hereditary nonpolyposis colorectal cancer, a condition associated with germ line DNA mismatch repair (MMR) gene defects, and is believed to be caused by rapid accumulation of replication errors in critical genes, such as the APC (adenomatous polyposis coli) tumor suppressor gene. To study the potential contribution of MMR genes to accelerated intestinal tumorigenesis, we crossed the Min mouse, heterozygous for a germ line mutation of Apc, with an MMR gene (Msh2)-deficient mouse. MSH2 deficiency resulted in the development of many colonic aberrant crypt foci, as well as reduced survival of the mice, secondary to both a greater number and more rapidly developing adenomas. The mechanism of inactivation of the wild-type Apc allele depended on MSH2 status. In the presence of functional MSH2, all tumors demonstrated loss of heterozygosity. In contrast, whereas all adenomas were APC negative by immunostaining, only 5 of 34 adenomas from Apc+/-/Msh2-/- mice demonstrated loss of heterozygosity of the wild-type Apc allele, suggesting that somatic Apc mutations are responsible for the additional tumors. These findings provide evidence for the important role of MMR genes in accelerated intestinal tumorigenesis, thus supporting more aggressive surveillance strategies to prevent colorectal cancer in hereditary nonpolyposis colorectal cancer.
Reitmair
A H
AH
Amgen Institute, Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Canada.
Cai
J C
JC
Bjerknes
M
M
Redston
M
M
Cheng
H
H
Pind
M T
MT
Hay
K
K
Mitri
A
A
Bapat
B V
BV
Mak
T W
TW
Gallinger
S
S
D000236:Adenoma / Q000235:genetics; D000818:Animals; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004276:DNA, Satellite / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D017353:Gene Deletion; D017491:Genes, APC; D018095:Germ-Line Mutation; D006579:Heterozygote; D007414:Intestinal Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051718:MutS Homolog 2 Protein; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics
D004273:DNA, Neoplasm; D004276:DNA, Satellite; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein