Mapping of loci providing genetic resistance to tumorigenesis and characterization of candidate genes

Abstract

Genome-wide screening by genetic marker analysis in crosses between well-characterized mouse strains may allow the identification of loci responsible for susceptibility and resistance to specific tumour types. The aim of this project was to carry out the mapping of cancer modifier loci controlling both skin and lung tumour phenotypes in a SWR x (SWR x Car-R) backcross population by genome-wide analysis of single nucleotide polymorphisms (SNPs). Through different experimental approaches, such as SNP library genotyping, genomic DNA subtraction and SNP array analysis we identified cancer modifier loci involved in skin or lung cancer susceptibility and characterized cancer modifier genes mapping in these associated regions. SNP library genotyping detected an association of the Par4 locus with lung tumorigenesis. Candidate gene analysis in this region revealed a nonconservative variation in Met gene, that highlighted its candidacy for the Par4 locus. Genomic subtraction identified a Chr.1 region, where genetic linkage analysis of 17 SNPs in individual mice confirmed the significant association of this region to skin and lung tumour susceptibility. By a candidate gene approach we focused on Igfbp5. In vitro characterization detected -4.0-fold inhibition of clonogenicity by Igfbp5 over-expression in human lung cancer cell lines and expression analysis in normal lung tissue revealed -2.0-fold higher transcript levels in resistant Car-R compared with susceptible SWR mice, revealing a 3 Supplied by The British Library - 'The world's knowledge' 1I .! j. f Abstract potential role of Igfbp5 gene in modulating lung tumorigenesis. Preliminary analysis of genome-wide scans using SNP arrays confirmed the Chr.1 and Chr.6 loci; the present pedigree analysis in the remaining genome may allow the identification of additional loci affecting lung and skin tumorigenesis, thus demonstrating that the susceptibility to both tumorigenesis result from a combination of several weak genetic loci. . In conclusion, genome-wide analysis in well-defined mice allowed the identification of QTLs and genes affecting lung and skin cancer susceptibility through a combination of methodologies.EThOS - Electronic Theses Online ServiceGBUnited Kingdo