Study ERP001454 Download

TitleAnalysis_of_genetically_and_chemically_induced_mouse_cancers
AbstractWe will sequence lung tumors induced by genetic activation of the Ras pathway with those induced by chemical carcinogens. In the KrasLA2 model, sporadic recombination leads to expression of a mutant Kras allele and development of adenocarcinomas. When bred into the FVB genetic background, this model gives rise to adenomas and adenocarcinomas that show increasing genetic instability with tumor size, a feature that was not seen in a mixed 129/C57BL/6 background. It is also possible to induce Kras mutant lung tumors using mutagens such as urethane. Carcinogen exposure plays a major role in human cancer incidence, and chemically induced tumors may be expected to have a higher point mutation frequency than those induced by germline manipulation. About 90% of urethane-induced tumors have the same activating mutation at codon 61 in Kras. These lung tumors offer a unique possibility to compare chemically and genetically induced tumors in the same genetic background (FVB/N) that are initiated by mutations in the same gene (Kras). By changing the nature of the inducing carcinogen, the mutation spectrum at the Kras locus can also be altered. For example, tumors induced by MNU or MNNG often exhibit activating transition mutations at codon 12 or 13 rather than codon 61 of Kras. This combination of mouse models offers a unique opportunity to investigate the spectrum of mutations that drive lung cancer development in the mouse as a result of genetic activation of Kras, or by mutation of the same oncogene using different chemical mutagens. Similar considerations have driven the selection of colon tumors for sequencing. Colon adenomas and carcinomas can be induced by genetic manipulation of a range of tumor suppressors or oncogenes, including Apc, Mlh1, Msh2, or by exposure to chemical mutagens. Loss of Apc function leads to activation of the Wnt/B-catenin pathway as an early event leading to adenoma formation and subsequent progression to carcinoma. The colonspecific carcinogen dimethylhyrdrazine (DMH), as well as the down-stream metabolite AOM, has proven useful in the investigation of the molecular mechanisms underlying the development of non-familial CRCs. Mice exposed to DMH or AOM develop colorectal tumors that accurately recapitulate pathologies seen in human CRC. AOM-induced tumors also result from activation of the WNT/CTNNB1 pathway. Unlike Apc-mediated models, AOMinduced tumors are primarily caused by mutations in Ctnnb1, which results in ubiquitination-resistant CTNNB1 and development of colorectal adenomas with increased expression of the key cell cycle regulators cyclin D1 (Ccnd1) and Myc.
Referencesno content
OrganismsMus musculus
TypeOther
DescriptionWe will sequence lung tumors induced by genetic activation of the Ras pathway with those induced by chemical carcinogens. In the KrasLA2 model, sporadic recombination leads to expression of a mutant Kras allele and development of adenocarcinomas. When bred into the FVB genetic background, this model gives rise to adenomas and adenocarcinomas that show increasing genetic instability with tumor size, a feature that was not seen in a mixed 129/C57BL/6 background. It is also possible to induce Kras mutant lung tumors using mutagens such as urethane. Carcinogen exposure plays a major role in human cancer incidence, and chemically induced tumors may be expected to have a higher point mutation frequency than those induced by germline manipulation. About 90% of urethane-induced tumors have the same activating mutation at codon 61 in Kras. These lung tumors offer a unique possibility to compare chemically and genetically induced tumors in the same genetic background (FVB/N) that are initiated by mutations in the same gene (Kras). By changing the nature of the inducing carcinogen, the mutation spectrum at the Kras locus can also be altered. For example, tumors induced by MNU or MNNG often exhibit activating transition mutations at codon 12 or 13 rather than codon 61 of Kras. This combination of mouse models offers a unique opportunity to investigate the spectrum of mutations that drive lung cancer development in the mouse as a result of genetic activation of Kras, or by mutation of the same oncogene using different chemical mutagens. Similar considerations have driven the selection of colon tumors for sequencing. Colon adenomas and carcinomas can be induced by genetic manipulation of a range of tumor suppressors or oncogenes, including Apc, Mlh1, Msh2, or by exposure to chemical mutagens. Loss of Apc function leads to activation of the Wnt/B-catenin pathway as an early event leading to adenoma formation and subsequent progression to carcinoma. The colonspecific carcinogen dimethylhyrdrazine (DMH), as well as the down-stream metabolite AOM, has proven useful in the investigation of the molecular mechanisms underlying the development of non-familial CRCs. Mice exposed to DMH or AOM develop colorectal tumors that accurately recapitulate pathologies seen in human CRC. AOM-induced tumors also result from activation of the WNT/CTNNB1 pathway. Unlike Apc-mediated models, AOMinduced tumors are primarily caused by mutations in Ctnnb1, which results in ubiquitination-resistant CTNNB1 and development of colorectal adenomas with increased expression of the key cell cycle regulators cyclin D1 (Ccnd1) and Myc. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
SubmitterThe Sanger Center
Related objects
SubmissionsERA131039
Linksno content