Genetic control of renal tumorigenesis by the mouse Rtm1 locus

BMC Genomics

Research Article

Alessia Bertolotti¹  Maurizio Colecchia¹  Antonella Galvan²  Tommaso Antonio Dragani²  Orlando Garcia Ribeiro³  Olga Célia Martinez Ibañez³  Andrea Borrego³  Wafa Hanna Koury Cabrera³  Marcelo De Franco³  José Ricardo Jensen³  Nancy Starobinas³ 

[1]Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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

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

关键词: Animal models;    Genetic linkage;    Inflammation;    Kidney cancer;    QTL;    SNPs;   

DOI  :  10.1186/1471-2164-14-724

 received in 2013-06-21, accepted in 2013-10-11,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsAIRmax 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.ConclusionsWe 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.

【 授权许可】

Unknown   
© Jensen et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.