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Open Access Research article

Genetic control of renal tumorigenesis by the mouse Rtm1 locus

José Ricardo Jensen1, Antonella Galvan2, Andrea Borrego1, Wafa Hanna Koury Cabrera1, Orlando Garcia Ribeiro1, Nancy Starobinas1, Marcelo De Franco1, Maurizio Colecchia3, Alessia Bertolotti3, Tommaso Antonio Dragani2 and Olga Célia Martinez Ibañez1*

Author Affiliations

1 Laboratory of Immunogenetics, Instituto Butantan, Avenida Dr. Vital Brazil, 1500, 05503-900 São Paulo, Brazil

2 Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

3 Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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BMC Genomics 2013, 14:724  doi:10.1186/1471-2164-14-724

Published: 22 October 2013

Abstract

Background

The genetic basis of susceptibility to renal tumorigenesis has not yet been established in mouse strains. Mouse lines derived by bidirectional phenotypic selection on the basis of their maximal (AIRmax) or minimal (AIRmin) acute inflammatory responsiveness differ widely in susceptibility to spontaneous and urethane-induced renal tumorigenesis. To map the functional loci modulating renal tumor susceptibility in these mice, we carried out a genome-wide genetic linkage study, using SNP arrays, in an (AIRmax x AIRmin)F2 intercross population treated with a single urethane dose at 1 week of age and phenotyped for renal tumors at 35 weeks of age.

Results

AIRmax mice did not develop renal tumors spontaneously nor in response to urethane, whereas in AIRmin mice renal tumors formed spontaneously (in 52% of animals) and after urethane induction (89%). The tumors had a papillary morphology and were positive for alpha-methylacyl-CoA racemase and negative for CD10. By analysis of 879 informative SNPs in 662 mice, we mapped a single quantitative trait locus modulating the incidence of renal tumors in the (AIRmax x AIRmin)F2 intercross population. This locus, which we named Renal tumor modifier QTL 1 (Rtm1), mapped to chromosome 17 at 23.4 Mb (LOD score = 15.8), with SNPs rs3696835 and rs3719497 flanking the LOD score peak. The A allele of rs3719497 from AIRmin mice was associated with a 2.5-fold increased odds ratio for renal tumor development. The LOD score peak included the Tuberous sclerosis 2 (Tsc2) gene which has already been implicated in kidney disease: loss of function by germline retroviral insertion is associated with spontaneous renal tumorigenesis in the Eker rat, and heterozygous-null Tsc2(+/-) mice develop renal cystadenomas.

Conclusions

We mapped Rtm1 as a single major locus modulating renal tumorigenesis in a murine intercross population. Thus, the AIR mouse lines can be considered a new genetic model for studying the role of germline and somatic molecular alterations in kidney neoplastic disease.

Keywords:
Animal models; Genetic linkage; Inflammation; Kidney cancer; QTL; SNPs