Differentially expressed genes in nonsmall cell lung cancer: expression profiling of cancer-related genes in squamous cell lung cancer

Kettunen, Eeva; Anttila, Sisko; Seppänen, Janne; Karjalainen, Antti; Edgren, Henrik; Lindström, Irmeli; Salovaara, Reijo; Nissén, Anna‐Maria; Salo, Jarmo A.; Mattson, K.; Hollmén, Jaakko; Knuutila, Sakari; Wikman, Harriet

doi:10.1016/s0165-4608(03)00300-5

Cited by 141 publications

(134 citation statements)

References 39 publications

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“…Differential region finding was used for the expression data in the same way as for array CGH. In addition, ROC analyses, which do not take chromosome position into account, were done to find possible target genes (17,18). Overall, 5.2% of the Affymetrix probe-set IDs (n = 1733), corresponding to 1,491 different genes, were found to be significantly differentially expressed (ROC < 0.2 or > 0.8 and P < 0.05).…”

Section: Resultsmentioning

confidence: 99%

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Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion

Wrage¹,

Ruosaari

Eijk

et al. 2009

Clinical Cancer Research

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Purpose: Bone marrow is a common homing organ for early disseminated tumor cells (DTC) and their presence can predict the subsequent occurrence of overt metastasis and survival in lung cancer. It is still unclear whether the shedding of DTC from the primary tumor is a random process or a selective release driven by a specific genomic pattern. Experimental Design: DTCs were identified in bone marrow from lung cancer patients by an immunocytochemical cytokeratin assay. Genomic aberrations and expression profiles of the respective primary tumors were assessed by microarrays and fluorescence in situ hybridization analyses. The most significant results were validated on an independent set of primary lung tumors and brain metastases. Results: Combination of DNA copy number profiles (array comparative genomic hybridization) with gene expression profiles identified five chromosomal regions differentiating bone marrownegative from bone marrow-positive patients (4q12-q32, 10p12-p11, 10q21-q22, 17q21, and 20q11-q13). Copy number changes of 4q12-q32 were the most prominent finding, containing the highest number of differentially expressed genes irrespective of chromosomal size (P = 0.018). Fluorescence in situ hybridization analyses on further primary lung tumor samples confirmed the association between loss of 4q and bone marrow-positive status. In bone marrowpositive patients, 4q was frequently lost (37% versus 7%), whereas gains could be commonly found among bone marrow-negative patients (7% versus 17%). The same loss was also found to be common in brain metastases from both small and non-small cell lung cancer patients (39%). Conclusions:Thus, our data indicate, for the first time, that early hematogenous dissemination of tumor cells might be driven by a specific pattern of genomic changes.Lung cancer is one of the most frequently diagnosed cancers in developed countries and the main cause of cancer-related deaths, with an overall relative 5-year survival rate of 15% (1). Approximately 40% of patients with completely resected nonsmall cell lung cancer (NSCLC) without lymph node metastasis (N 0 ) or clinical signs of overt distant metastases (M 0 ) at time of the primary surgery relapse within 24 months.

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Section: Resultsmentioning

confidence: 99%

“…In addition, receiver operating characteristic (ROC) curves were used to identify individual genes that were differentially expressed between bone marrow-positive and bone marrow-negative patients independent of chromosomal localization (17,18).…”

Section: Translational Relevancementioning

confidence: 99%

Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion

Wrage¹,

Ruosaari

Eijk

et al. 2009

Clinical Cancer Research

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“…As the first step, AUROC (ROC) analysis model (Kettunen et al, 2004) was chosen owing to similar size of the two exposure groups. Genes with ROC values less than 0.4, or higher than 0.6, and with P-value less than 0.4 were included in the subsequent analyses.…”

Section: Patient Materialsmentioning

confidence: 99%

Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer

et al. 2007

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Asbestos is a pulmonary carcinogen known to give rise to DNA and chromosomal damage, but the exact carcinogenic mechanisms are still largely unknown. In this study, gene expression arrays were performed on lung tumor samples from 14 heavily asbestos-exposed and 14 nonexposed patients matched for other characteristics. Using a two-step statistical analysis, 47 genes were revealed that could differentiate the tumors of asbestos-exposed from those of non-exposed patients. To identify asbestosassociated regions with DNA copy number and expressional changes, the gene expression data were combined with comparative genomic hybridization microarray data. As a result, a combinatory profile of DNA copy number aberrations and expressional changes significantly associated with asbestos exposure was obtained. Asbestosrelated areas were detected in 2p21-p16. 3, 3p21.31, 5q35.2-q35.3, 16p13.3, 19p13.3-p13.1 and 22q12.3-q13.1. The most prominent of these, 19p13, was further characterized by microsatellite analysis in 62 patients for the differences in allelic imbalance (AI) between the two groups of lung tumors. 79% of the exposed and 45% of the non-exposed patients (P ¼ 0.008) were found to be carriers of AI in their lung tumors. In the exposed group, AI in 19p was prevalent regardless of the histological tumor type. In adenocarcinomas, AI in 19p appeared to occur independently of the asbestos exposure.

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“…Decreased expression of KLF6 has been associated with poor prognosis in lung adenocarcinoma and prostate cancer. 30,[36][37][38][39] The role that KLF6 polymorphisms play in increasing the risk of developing prostate cancer is also controversial. Narla et al 40 proposed that the presence of a germline single-nucleotide polymorphism (SNP) (IVS1 -27G4A) in KLF6 could produce a splicing variant that would reduce the activation of p21.…”

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KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

et al. 2008

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Krü ppel-like factor 6 (KLF6) has been reported to act as a tumor suppressor gene involved in the regulation of the cell cycle by activating p21 in a p53-independent manner. Many studies suggest that KLF6 is inactivated by allelic loss and somatic mutation. However, there is a high variability in the reported frequency of mutations (from 1 to 55%). TP53 also regulates the cell cycle through the activation of p21. In prostate cancer, the reported frequency of TP53 mutations ranges from 3 to 42%. In all these reports, there is a considerable degree of methodological heterogeneity. Our aim was to determine the frequency of KLF6 and TP53 mutations in a welldefined group of prostate tumors with different stages and Gleason grades. The four exons of KLF6 and exons 4-9 of TP53 were studied in 103 cases, including 90 formalin-fixed, paraffin-embedded (FFPE) and 13 frozen samples. All tumors were analyzed through PCR and direct sequencing. All changes found were confirmed by a second independent PCR and sequencing reaction. For KLF6, mutation (E227G) was only detected in one tumor (1%) and for TP53, three different mutations (L130H, H214R, and Y234C) were detected in five tumors (5%). This low mutation index is in keeping with recent papers on the subject. Our study strongly supports the notion that KLF6 and TP53 mutations are not frequent events in prostate cancer. When using FFPE tissues, it is mandatory to perform at least two independent rounds of PCR and sequencing to confirm mutations and exclude Taq polymerase-induced artifacts. Two of these genes are Krü ppel-like factor 6 (KLF6) and TP53.KLF6 is a transcription factor that interacts with DNA through three zinc-fingers in its COOHterminal domain. KLF6 belongs to the KLF family, a family that is broadly involved in cell differentiation, development, growth-related signal transduction, cell proliferation, apoptosis, and angiogenesis. 5 It has been suggested that KLF6 could be involved in the regulation of the cell cycle by activating p21 in a p53-independent manner. 6 This has been proven in several in vitro 5 and in vivo assays. 7 KLF6 is believed to regulate cancer development and progression through the downregulation of the c-Jun oncoprotein 8 and the activation of E-cadherin. 9 The reported frequency of KLF6 mutations in different types of human cancer varies in the different published studies. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] In prostate cancer, four studies have analyzed the frequency of KLF6 mutations. 6,[30][31][32] In the first published study, Narla et al 6 showed a very high frequency, 55%, whereas in the following study, Chen et al 30 obtained a lower frequency, around 15%. The results of two recent reports provided frequencies of 0 and 1%. 31,32 It should be noted that there were considerable

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Differentially expressed genes in nonsmall cell lung cancer: expression profiling of cancer-related genes in squamous cell lung cancer

Cited by 141 publications

References 39 publications

Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion

Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion

Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer

KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

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