Exome_sequencing_of_radiation_induced_mouse_lymphomas

Radiation-induced mouse thymic lymphomas have been shown to be a versatile model to study tumor development (e.g. Perez-Losada et al., Oncogene, 2003; Mao et al., Nature, 2004; Mao et al., Cancer Cell, 2007). The range of mutations that occur in these tumors is related to human disease, and importantly, using targeted knock-out models the temporal and causative sequence of mutations acquired during lymphomagenesis can be traced. Instrumental for these experiments are a backcross population of radiation resistant SPRET spretus strain mice and 129/Sv musculus mice with hetero- or homozygous loss of Trp53. While Trp53 wild-type mice are relatively resistant to a single dose of 4 Gy gamma irradiation, mice heterozygous for an inactivated Trp53 allele rapidly develop tumors in radiation sensitive tissues such as thymus and spleen. Tumor development is further accelerated in Trp53 null mice (Kemp et al, Cell, 1994). Analyses of CGH and microsatellite resolution LOH data from these lymphomas have shown specific patterns of genomic alterations suggesting distinct progression models relating to Trp53 germline background. For instance, lymphomas from Trp53 heterozygous mice, but not those from Trp53 null mice, frequently show LOH and mutations of the tumor suppressor gene Fbxw7 (Mao et al, Nature, 2004). We have generated combined gene expression and LOH profiles for 48 radiation-induced lymphomas (22 from Trp53+/- and 26 from Trp53-/- mice). Our initial data analysis have identified sample subgroups that partly reflect the host Trp53 background but also point to the importance of additional events, e.g. loss of Pten expression or function, previously shown to be independent of Trp53 host status (Mao et al., Oncogene, 2003). Furthermore, network analysis of the gene expression data suggests differential roles and regulation of central signaling pathways depending on Trp53 background. By also acquiring sequence level data for the exomes of these tumors we expect to further elucidate the multi-step, multi-gene process of lymphomagenesis. Specifically, we would be interested in the following short aims: (i) Identify somatic genetic alterations to known and candidate tumor suppressors and oncogenes in relation to host Trp53 genotype. (ii) Identify specific 129/Sv and SPRET SNPs that affect the survival time of mice post radiation. Analyses will be performed with a special focus on previously identified frequently altered genomic regions (Mao et al, Nature, 2004). (iii) Identify mutations and SNPs that can explain partition of samples into discrete groups based on gene expression profiles. (iv) By using a systems genetics approach, identify SNPs and mutations that relate to and are in control of gene expression networks.