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Induction of Renal Tumorigenesis with Elevated Levels of Somatic Loss of Heterozygosity in Tsc1^+/- Mice on a Blm-Deficient Background

Department of Medical Genetics, Cardiff University, Heath Park, Cardiff, United Kingdom

Requests for reprints: Jeremy P. Cheadle, Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, United Kingdom. Phone: 44-29-207-42652; Fax: 44-29-207-46551; E-mail: cheadlejp{at}cardiff.ac.uk.

A Bloom's deficient mouse model (Blm^m3/m3) has been shown to induce colorectal tumorigenesis when crossed with Apc^+/Min mice. Here, we investigated whether the Blm^m3/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 24% excess of Tsc1^+/– over Tsc1^+/+ mice died before weaning (P = 0.016), although Blm deficiency had no cumulative effect on Tsc1^+/– survival. Tsc1^+/– Blm^m3/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 (Tsc1^wt) 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 Tsc1^wt allele (P = 0.03). Ninety-five percent (19 of 20) of lesions from Tsc1^+/– Blm^+/m3 mice retained the wild-type Blm (Blm^wt) 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 (Ser^240/244), suggesting that these lesions develop through the normal pathway of Tsc-associated tumorigenesis. This work shows the use of the Blm^m3/m3 mice for inducing renal tumorigenesis, and the high levels (87%) of LOH in the resultant tumors will help facilitate mapping of loci involved in tumor progression.

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