Intestinal and extra-intestinal tumor multiplicities in the Apc1638N mouse model after exposure to X-rays.
Seven-week-old Apc1638N mice were exposed to a single dose of 5 Gy total-body X-irradiation resulting in a 8-fold increase in the number of intestinal tumors and a reduction of the lifespan to an average of 6 months. The distribution of tumors along the intestinal tract as well as the adenoma/carcinoma ratio, were similar between non-irradiated and irradiated animals. Semi-quantitative PCR analysis of intestinal-tumor DNA revealed that 10 out of 14 tumors had lost the wild-type Apc allele. However, in contrast to spontaneous Apc1638N intestinal tumors in which the LOH event at the Apc locus involves the entire chromosome 18 (1), in 6 out of 10 tumors derived from X-irradiated animals the Apc loss is associated with only a partial intrachromosomal deletion. The remaining tumors have lost all chromosome 18 markers tested. In addition to the intestinal tumors, female Apc1638N mice are susceptible to the development of mammary tumors. Upon X-irradiation, Apc1638N mice show a striking 15-fold increase in mammary tumors. Moreover, Apc1638N mice spontaneously develop other extra-intestinal neoplasia, such as desmoid-like lesions similar to those associated with familial adenomatous polyposis (FAP), the human syndrome caused by germline mutations in the APC gene. Spontaneous desmoid growth is sex-dependent, as male Apc1638N mice develop 3-fold more desmoids than female mice. Interestingly, X-irradiation seemed to increase the number of desmoids per animal nearly twofold only in female Apc1638N mice. Five out of 9 desmoids found in Apc1638N mice exposed to X-ray displayed loss of the wild-type Apc allele.
van der Houven van Oordt
C W
CW
Department of Molecular Carcinogenesis, Leiden University, The Netherlands.
Smits
R
R
Williamson
S L
SL
Luz
A
A
Khan
P M
PM
Fodde
R
R
van der Eb
A J
AJ
Breuer
M L
ML
D000483:Alleles; D000818:Animals; D005260:Female; D016368:Frameshift Mutation; D017491:Genes, APC; D007414:Intestinal Neoplasms / Q000209:etiology* / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000235:genetics; D014916:Whole-Body Irradiation; D014965:X-Rays