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 ORCID: https://orcid.org/0000-0002-2902-2348 and Cheadle, Jeremy Peter ORCID: https://orcid.org/0000-0001-9453-8458 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:	17 Oct 2022 08:27
URI:	https://orca.cardiff.ac.uk/id/eprint/181

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