A Sleeping Beauty transposon-mediated screen identifies murine susceptibility genes for adenomatous polyposis coli (
            <i>Apc</i>
            )-dependent intestinal tumorigenesis

Starr, Timothy K.; Scott, Patricia M.; Marsh, Benjamin M.; Zhao, Lei; Than, B L N; O’Sullivan, M. Gerard; Sarver, Aaron L.; Dupuy, Adam J.; Largaespada, David A.; Cormier, Robert T.

doi:10.1073/pnas.1018012108

Cited by 67 publications

(69 citation statements)

References 42 publications

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“…By mapping the orientation of the transposon with respect to the orientation of the mutated gene, the majority of pancreatic tumor CCGs are predicted to function as TS genes (Datasets S1 and S2). This finding is similar to what has been observed for CCGs identified in transposon screens performed in other types of solid tumors (20)(21)(22), but it is in contrast to what is observed in hematopoietic tumors, where the majority of CCGs seem to function as oncogenes (23).…”

Section: Sequence Analysis Of Transposon Insertion Sites Identifies Pmentioning

confidence: 29%

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Mann

Ward

Yew

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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202

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Pancreatic cancer is one of the most deadly cancers affecting the Western world. Because the disease is highly metastatic and difficult to diagnosis until late stages, the 5-y survival rate is around 5%. The identification of molecular cancer drivers is critical for furthering our understanding of the disease and development of improved diagnostic tools and therapeutics. We have conducted a mutagenic screen using Sleeping Beauty (SB) in mice to identify new candidate cancer genes in pancreatic cancer. By combining SB with an oncogenic Kras allele, we observed highly metastatic pancreatic adenocarcinomas. Using two independent statistical methods to identify loci commonly mutated by SB in these tumors, we identified 681 loci that comprise 543 candidate cancer genes (CCGs); 75 of these CCGs, including Mll3 and Ptk2, have known mutations in human pancreatic cancer. We identified point mutations in human pancreatic patient samples for another 11 CCGs, including Acvr2a and Map2k4. Importantly, 10% of the CCGs are involved in chromatin remodeling, including Arid4b, Kdm6a, and Nsd3, and all SB tumors have at least one mutated gene involved in this process; 20 CCGs, including Ctnnd1, Fbxo11, and Vgll4, are also significantly associated with poor patient survival. SB mutagenesis provides a rich resource of mutations in potential cancer drivers for cross-comparative analyses with ongoing sequencing efforts in human pancreatic adenocarcinoma. P ancreatic ductal adenocarcinoma is one of the most deadly forms of cancer. In the United States, the rate of mortality is nearly equal to the rate of new diagnoses (1). Early disease detection is rare, and of those patients diagnosed with early-stage disease, only 20% are candidates for surgical resection. Approximately 50% of patients develop highly metastatic disease, for which current treatment regimens provide little increase in longevity (2). Clearly, there is a need for better biomarkers of disease and the identification of new therapeutic targets, particularly for metastatic disease.Human pancreatic cancer develops from preinvasive neoplasias, typically intraepithelial neoplasias (PanINs), although intraductal papillary mucinous neoplasia and mucinous cystic neoplasia can also give rise to adenocarcinoma (3). The majority of pancreatic adenocarcinoma is of ductal origin and contains a large desmoplastic component thought to promote tumorigenesis by modulating the tumor microenvironment. Oncogenic KRAS mutations are found in 90% of human tumors, and they appear in early PanIN (4). The accumulation of additional inactivating driver mutations in P16/CDKN2A, TP53, and SMAD4 occurs with high frequency in later-stage PanIN, and these mutations are likely required for tumor progression to invasive adenocarcinoma.Recent high-throughput sequencing efforts have shown that the majority of somatic point mutations in primary pancreatic adenocarcinoma are missense mutations and that most occur at low frequency (5). Pancreatic cancers exhibit a very unstable genome, and through whole-genome...

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Section: Sequence Analysis Of Transposon Insertion Sites Identifies Pmentioning

confidence: 29%

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Mann

Ward

Yew

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

202

219

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“…Discussion SB mutagenesis is a powerful tool that allows for the unbiased discovery of genes linked to cancer, with previous studies successfully using this approach in several cancer types (13,(26)(27)(28)(29)(30). In this study, we used the SB model to identify candidate genes driving the development of MB in conjunction with a mutation in Ptch1.…”

Section: −20mentioning

confidence: 99%

Sleeping Beauty mutagenesis in a mouse medulloblastoma model defines networks that discriminate between human molecular subgroups

Genovesi

Davis

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The Sleeping Beauty (SB) transposon mutagenesis screen is a powerful tool to facilitate the discovery of cancer genes that drive tumorigenesis in mouse models. In this study, we sought to identify genes that functionally cooperate with sonic hedgehog signaling to initiate medulloblastoma (MB), a tumor of the cerebellum. By combining SB mutagenesis with Patched1 heterozygous mice (Ptch1 lacZ/+ ), we observed an increased frequency of MB and decreased tumor-free survival compared with Ptch1 lacZ/+ controls. From an analysis of 85 tumors, we identified 77 common insertion sites that map to 56 genes potentially driving increased tumorigenesis. The common insertion site genes identified in the mutagenesis screen were mapped to human orthologs, which were used to select probes and corresponding expression data from an independent set of previously described human MB samples, and surprisingly were capable of accurately clustering known molecular subgroups of MB, thereby defining common regulatory networks underlying all forms of MB irrespective of subgroup. We performed a network analysis to discover the likely mechanisms of action of subnetworks and used an in vivo model to confirm a role for a highly ranked candidate gene, Nfia, in promoting MB formation. Our analysis implicates candidate cancer genes in the deregulation of apoptosis and translational elongation, and reveals a strong signature of transcriptional regulation that will have broad impact on expression programs in MB. These networks provide functional insights into the complex biology of human MB and identify potential avenues for intervention common to all clinical subgroups.

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“…Transposon-mediated mutagenesis has emerged as a powerful methodology for functionally annotating cancer genomes. A number of studies have utilized transposon-based insertional mutagenesis screens in mice to identify and validate a number of genes relevant to tumorigenesis, including T-cell leukemia, hepatocellular carcinoma, medulloblastoma, and nerve sheath tumors (14)(15)(16)(17)(18)(19)(20)(21). To date, a vast majority of studies have relied upon the mobilization of mutagenic DNA transposons such as Sleeping Beauty (SB) or piggyBac in transgenic mouse models.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Ex Vivo Transposon Mutagenesis Identifies Genes That Promote Growth Factor Independence and Leukemogenesis

et al. 2016

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Aberrant signaling through cytokine receptors and their downstream signaling pathways is a major oncogenic mechanism underlying hematopoietic malignancies. To better understand how these pathways become pathologically activated and to potentially identify new drivers of hematopoietic cancers, we developed a high-throughput functional screening approach using ex vivo mutagenesis with the Sleeping Beauty transposon. We analyzed over 1,100 transposon-mutagenized pools of Ba/F3 cells, an IL3-dependent pro-B-cell line, which acquired cytokine independence and tumor-forming ability. Recurrent transposon insertions could be mapped to genes in the JAK/ STAT and MAPK pathways, confirming the ability of this strategy to identify known oncogenic components of cytokine signaling pathways. In addition, recurrent insertions were identified in a large set of genes that have been found to be mutated in leukemia or associated with survival, but were not previously linked to the JAK/STAT or MAPK pathways nor shown to functionally contribute to leukemogenesis. Forced expression of these novel genes resulted in IL3-independent growth in vitro and tumorigenesis in vivo, validating this mutagenesis-based approach for identifying new genes that promote cytokine signaling and leukemogenesis. Therefore, our findings provide a broadly applicable approach for classifying functionally relevant genes in diverse malignancies and offer new insights into the impact of cytokine signaling on leukemia development.

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A Sleeping Beauty transposon-mediated screen identifies murine susceptibility genes for adenomatous polyposis coli ( Apc )-dependent intestinal tumorigenesis

Cited by 67 publications

References 42 publications

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Sleeping Beauty mutagenesis in a mouse medulloblastoma model defines networks that discriminate between human molecular subgroups

Comprehensive Ex Vivo Transposon Mutagenesis Identifies Genes That Promote Growth Factor Independence and Leukemogenesis

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