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      Suppression of Lung Adenocarcinoma Progression by Nkx2-1

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          Abstract

          Despite the high prevalence and poor outcome of patients with metastatic lung cancer, the mechanisms of tumour progression and metastasis remain largely uncharacterized. We modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS 1 and inactivation of the p53-pathway 2, using conditional alleles in mice 35. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras LSL-G12D/+;p53 flox/flox mice initiates lung adenocarcinoma development 4. Although tumours are initiated synchronously by defined genetic alterations, only a subset become malignant, suggesting that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK-2 related homeobox transcription factor Nkx2-1 (Ttf-1/Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1-negativity is pathognomonic of high-grade poorly differentiated tumours. Gain-and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1 regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically-restricted chromatin regulator Hmga2. While focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function 69, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability, and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of Nkx2-1 in the same tumour type substantiate its role as a dual function lineage factor.

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          Most cited references 22

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          Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome.

          The p53 tumor suppressor gene is commonly altered in human tumors, predominantly through missense mutations that result in accumulation of mutant p53 protein. These mutations may confer dominant-negative or gain-of-function properties to p53. To ascertain the physiological effects of p53 point mutation, the structural mutant p53R172H and the contact mutant p53R270H (codons 175 and 273 in humans) were engineered into the endogenous p53 locus in mice. p53R270H/+ and p53R172H/+ mice are models of Li-Fraumeni Syndrome; they developed allele-specific tumor spectra distinct from p53+/- mice. In addition, p53R270H/- and p53R172H/- mice developed novel tumors compared to p53-/- mice, including a variety of carcinomas and more frequent endothelial tumors. Dominant effects that varied by allele and function were observed in primary cells derived from p53R270H/+ and p53R172H/+ mice. These results demonstrate that point mutant p53 alleles expressed under physiological control have enhanced oncogenic potential beyond the simple loss of p53 function.
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            Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study.

            Although prognostic gene expression signatures for survival in early-stage lung cancer have been proposed, for clinical application, it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training-testing, multi-site, blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression either alone or combined with basic clinical covariates (stage, age, sex) could be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. Most methods performed better with clinical data, supporting the combined use of clinical and molecular information when building prognostic models for early-stage lung cancer. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas.
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              Characterizing the cancer genome in lung adenocarcinoma.

              Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in approximately 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                14 February 2011
                6 April 2011
                5 May 2011
                5 November 2011
                : 473
                : 7345
                : 101-104
                Affiliations
                [1 ] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
                [2 ] Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
                [3 ] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
                [4 ] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
                [5 ] Dana-Farber Cancer Institute, Harvard University, Cambridge, Massachusetts, USA
                [6 ] Broad Institute, Cambridge, Massachusetts, USA
                [7 ] Department of Biomedical Sciences, Tufts University Veterinary School, North Grafton, Massachusetts, USA
                [8 ] Department of Genetics, University of North Carolina, North Carolina, USA
                Author notes
                Correspondence and requests for materials should be addressed to T.J., tjacks@ 123456mit.edu
                Article
                nihpa269264
                10.1038/nature09881
                3088778
                21471965

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: National Cancer Institute : NCI
                Funded by: Howard Hughes Medical Institute
                Award ID: R01 CA109038 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: Howard Hughes Medical Institute
                Award ID: P30 CA014051-40 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: Howard Hughes Medical Institute
                Award ID: P30 CA014051-39 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: Howard Hughes Medical Institute
                Award ID: P30 CA014051-38 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: Howard Hughes Medical Institute
                Award ID: P30 CA014051-37 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: Howard Hughes Medical Institute
                Award ID: P30 CA014051-36 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: Howard Hughes Medical Institute
                Award ID: ||HHMI_
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