Expression Profile–Defined Classification of Lung Adenocarcinoma Shows Close Relationship With Underlying Major Genetic Changes and Clinicopathologic Behaviors

Takeuchi, Toshiyuki; Tomida, Shuta; Yatabe, Yasushi; Kosaka, Takayuki; Osada, Hiroyuki; Yanagisawa, Kiyoshi; Mitsudomi, Tetsuya; Takahashi, Takashi

doi:10.1200/jco.2005.03.8224

Cited by 288 publications

(307 citation statements)

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“…Characterization of the 45-gene metastatic signature using gene ontology terms In order to gain functional insight into how the metastasis signature genes might contribute in the acquisition of metastatic potential in LNM35, we therefore employed our Gene Ontology (GO) term identifier of functions and other characteristics that are utilized in association with certain phenotypes of interest (Takeuchi et al, 2006). With this identifier, we found that GO terms related to four biological processes, three molecular functions and one cellular component were significantly more frequently observed than expected (Po0.005), when the frequency of a GO term appearing in the 45-gene metastatic signature was compared with that in the entire set of 8644 unique genes on the microarrays used in this study ( Table 2).…”

Section: Identification Of Genes Associated With the Acquisition Of Mmentioning

confidence: 99%

“…2000) analysis was employed to highlight functionally distinct biological features of a gene set associated with the acquisition of invasive and metastatic capabilities in LNM35, as described previously (Takeuchi et al, 2006). Briefly, database files used for this GO analysis were downloaded from the UniGene ftp site.…”

Section: Microarray Data Acquisition and Analysesmentioning

confidence: 99%

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Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach

et al. 2007

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Although widespread metastasis is the major cause of human lung cancer-related deaths, its underlying mechanism remains largely unclear. Our genome-wide comparison of the expression profiles of a highly metastatic lung cancer cell line, NCI-H460-LNM35 (LNM35), and its parental clone, NCI-H460-N15 (N15), resulted in the identification of a cancer metastasis signature composed of 45 genes. Through gene ontology analysis, our study also provided insights into how this 45-gene metastasis signature may contribute to the acquisition of metastatic potential. By applying the signature to datasets of human cancer cases, we could demonstrate significant associations with a subset of cases with poor prognosis not only for the two datasets of cancers of the lung but also for cancers of the breast. Furthermore, we were able to show that enforced expression of the DLX4 homeobox gene, which was identified as a gene with significant downregulation in LNM35 as well as with significant association with favorable prognosis for lung cancer patients, markedly inhibited in vitro motility and invasion as well as in vivo metastasis via both hematogenous and lymphogenous routes. Taken together, these findings indicate that our combined transcriptome analysis is an efficient approach in the search for genes possessing both clinical usefulness in terms of prognostic prediction in human cancer cases and clear functional relevance for studying cancer biology in relation to metastasis.

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Section: Identification Of Genes Associated With the Acquisition Of Mmentioning

confidence: 99%

Section: Microarray Data Acquisition and Analysesmentioning

confidence: 99%

Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach

et al. 2007

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“…For survival analysis of LDHB gene expression, LDHB expression and survival data were previously published (Gene Expression Omnibus GSE11969; ref. 22). LDHB expression was mean-centered across all tumors then separated by above or below the mean.…”

Section: Survival Analysismentioning

confidence: 99%

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

McCleland¹,

Adler²,

Deming³

et al. 2013

Clinical Cancer Research

106

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Purpose: This study is aimed to identify genes within the KRAS genomic amplicon that are both coupregulated and essential for cell proliferation when KRAS is amplified in lung cancer.Experimental Design: We used an integrated genomic approach to identify genes that are coamplified with KRAS in lung adenocarcinomas and subsequently preformed an RNA interference (RNAi) screen to uncover functionally relevant genes. The role of lactate dehydrogenase B (LDHB) was subsequently investigated both in vitro and in vivo by siRNA and short hairpin RNA (shRNA)-mediated knockdown in a panel of lung adenocarcinoma cells lines. LDHB expression was also investigated in patient tumors using microarray and immunohistochemistry analyses.Results: RNAi-mediated depletion of LDHB abrogated cell proliferation both in vitro and in xenografted tumors in vivo. We find that LDHB expression correlates to both KRAS genomic copy number gain and KRAS mutation in lung cancer cell lines and adenocarcinomas. This correlation between LDHB expression and KRAS status is specific for lung cancers and not other tumor types that harbor KRAS mutations. Consistent with a role for LDHB in glycolysis and tumor metabolism, KRAS-mutant lung tumors exhibit elevated expression of a glycolysis gene signature and are more dependent on glycolysis for proliferation compared with KRAS wild-type lung tumors. Finally, high LDHB expression was a significant predictor of shorter survival in patients with lung adenocarcinomas.Conclusion: This study identifies LDHB as a regulator of cell proliferation in a subset of lung adenocarcinoma and may provide a novel therapeutic approach for treating lung cancer.

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Section: Introductionmentioning

confidence: 99%

“…Genetic alterations involved in the pathogenesis of lung cancer produce proteins involved in cell growth, invasion/ metastasis, differentiation, cell cycle processes, apoptosis and angiogenesis. Discovering these mechanisms and pathways will undoubtedly lead to new ways in dealing with prevention, early detection and therapy, for example, expression profiling can subclassify lung adenocarcinoma in terms of predicting length of survival [3].A number of potential biomarkers have recently been identified, but currently, no satisfactory biomarkers are available to screen for lung cancer due to low specificity and sensitivity [4,5]. Lung cancer biomarkers have the potential to be involved in patient screening, monitoring of cancer progression, treatment response and as a predictive factor for Correspondence: Dr. Paul Dowling, The National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland E-mail: paul.dowling@dcu.ie Fax: 1353-1-7005484…”

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confidence: 99%

2‐D difference gel electrophoresis of the lung squamous cell carcinoma versus normal sera demonstrates consistent alterations in the levels of ten specific proteins

et al. 2007

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Research Article 2-D difference gel electrophoresis of the lung squamous cell carcinoma versus normal sera demonstrates consistent alterations in the levels of ten specific proteinsMost lung cancers are diagnosed too late for curative treatment to be possible, therefore early detection is crucial. Serum proteins are a rich source of biomarkers and have the potential to be used as diagnostic and prognostic indicators for lung cancer. In order to examine differences in serum levels of specific proteins associated with human lung squamous carcinoma, immunodepletion of albumin and five other high-abundant serum proteins followed by 2-D difference gel electrophoresis (DIGE) analysis and subsequent MS was used to generate a panel of proteins found to be differentially expressed between the cancer and normal samples. Proteins found to have increased abundance levels in squamous cell carcinoma sera compared to normal sera included apolipoprotein A-IV precursor, chain F; human complement component C3c, haptoglobin, serum amyloid A protein precursor and Ras-related protein Rab-7b. Proteins found to have lower abundance levels in squamous cell carcinoma sera compared to normal sera included alpha-2-HS glycoprotein, hemopexin precursor, proapolipoprotein, antithrombin III and SP40; 40. The data presented here demonstrate that high-abundant protein removal combined with 2-D DIGE is a powerful strategy for the discovery of potential biomarkers. The identification of lung cancer-specific biomarkers is crucial to early detection, which in turn could lead to a dramatic increase in survival rates. IntroductionOver 1 million people are diagnosed with lung cancer each year [1]. Most lung cancer is diagnosed too late for curative treatment to be possible. Efforts at early detection and treatment have had little success to date and hence the overall prognosis remains poor. In the majority of those diagnosed with lung cancer, the disease has already metastasised at the time of diagnosis. Lung cancer comprises broadly of two groups, small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). NSCLC comprises more than 80% of lung cancers including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, with squamous carcinoma being the most common type.A major factor in the high mortality of lung cancer patients is the presence of metastatic tumours in approximately two-thirds of patients at time of diagnosis [2]. Detection of cancer in these patients at earlier stages would increase survival rates dramatically. The identification of lung cancer-specific biomarkers is critical to early detection. The pathophysiology of lung squamous cell carcinoma development is complex and incompletely understood. Genetic alterations involved in the pathogenesis of lung cancer produce proteins involved in cell growth, invasion/ metastasis, differentiation, cell cycle processes, apoptosis and angiogenesis. Discovering these mechanisms and pathways will undoubtedly lead to new ways in dealing with prevention, early detection an...

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Expression Profile–Defined Classification of Lung Adenocarcinoma Shows Close Relationship With Underlying Major Genetic Changes and Clinicopathologic Behaviors

Cited by 288 publications

References 25 publications

Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach

Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

2‐D difference gel electrophoresis of the lung squamous cell carcinoma versus normal sera demonstrates consistent alterations in the levels of ten specific proteins

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