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Induction of renal tumorigenesis with elevated levels of somatic loss of heterozygosity in Tsc1+/- mice on a Blm-deficient background

Wilson, Catherine Helen, Idziaszczyk, Shelley Alexis, Colley, James, Humphreys, Vikki, Guy, Carol, Maynard, Julie Helen, Sampson, Julian Roy and Cheadle, Jeremy Peter 2005. Induction of renal tumorigenesis with elevated levels of somatic loss of heterozygosity in Tsc1+/- mice on a Blm-deficient background. Cancer Research 65 (22) , pp. 10179-10182. 10.1158/0008-5472.CAN-05-2688

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Abstract

A Bloom’s deficient mouse model (Blmm3/m3) has been shown to induce colorectal tumorigenesis when crossed with Apc+/Min mice. Here, we investigated whether the Blmm3/m3 genotype could induce tumorigenesis in extracolonic tissues in tuberous sclerosis 1–deficient (Tsc1+/) mice that are predisposed to renal cystadenomas and carcinomas. Genotyping of offspring from Tsc1+/ Blm+/m3 intercrosses showed that a f24% excess of Tsc1+/ over Tsc1+/+ mice died before weaning (P = 0.016), although Blm deficiency had no cumulative effect on Tsc1+/ survival. Tsc1+/ Blmm3/m3 mice had significantly more macroscopic and microscopic renal lesions at 3 to 6 months compared with Tsc1+/ Blm+/m3 mice (P =0.0003 and 0.0203, respectively), and their tumors showed significantly increased levels of somatic loss of heterozygosity (LOH) of the wild-type Tsc1 (Tsc1wt) allele compared with those from Tsc1+/ Blm+/+ mice (P < 0.0001). Tsc1+/ Blm+/m3 mice did not show significantly more renal lesions compared with Tsc1+/ Blm+/+ animals; however, their lesions still showed significantly increased levels of somatic LOH of the Tsc1wt allele (P = 0.03). Ninety-five percent (19 of 20) of lesions from Tsc1+/ Blm+/m3 mice retained the wild-type Blm (Blmwt) allele, indicating that the increased somatic LOH at Tsc1 was mediated by Blm haploinsufficiency. Renal lesions from a Blm-deficient background stained positively with anti-phospho-S6 ribosomal protein (Ser240/244), suggesting that these lesions develop through the normal pathway of Tsc-associated tumorigenesis. This work shows the use of the Blmm3/m3 mice for inducing renal tumorigenesis, and the high levels (f87%) of LOH in the resultant tumors will help facilitate mapping of loci involved in tumor progression. (Cancer Res 2005; 65(22): 10179-82)

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
Publisher: American Association for Cancer Research
ISSN: 1538-7445
Last Modified: 12 Jun 2019 02:16
URI: http://orca-mwe.cf.ac.uk/id/eprint/181

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