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dc.contributor.authorVonlanthen, S
dc.contributor.authorHeighway, Jim
dc.contributor.authorTschan, M P
dc.contributor.authorBorner, M M
dc.contributor.authorAltermatt, H J
dc.contributor.authorKappeler, A
dc.contributor.authorTobler, A
dc.contributor.authorFey, M F
dc.contributor.authorThatcher, Nick
dc.contributor.authorYarbrough, W G
dc.contributor.authorBetticher, Daniel C
dc.date.accessioned2010-02-12T15:43:27Z
dc.date.available2010-02-12T15:43:27Z
dc.date.issued1998-11-26
dc.identifier.citationExpression of p16INK4a/p16alpha and p19ARF/p16beta is frequently altered in non-small cell lung cancer and correlates with p53 overexpression. 1998, 17 (21):2779-85 Oncogeneen
dc.identifier.issn0950-9232
dc.identifier.pmid9840942
dc.identifier.doi10.1038/sj.onc.1202501
dc.identifier.urihttp://hdl.handle.net/10541/92007
dc.description.abstractThe CDKN2 locus expresses two different mRNA transcripts, designated alpha and beta. The protein product of the alpha transcript is the cell cycle inhibitor and tumour suppressor p16INK4a. The beta transcript is translated in an alternate reading frame (ARF) and in humans encodes a 15 kDa protein (p19ARF). Immunohistochemical and Western analysis of p16INK4a has shown that the protein is downregulated in a significant number of tumours, but less is known on the expression of the p19ARF. We have examined the expression of p16INK4a and p19ARF in resectable non-small cell lung cancer (NSCLC) by immunostaining (n=49) and multiplex RT-PCR (n=28). In order to investigate the mechanism responsible for p16INK4a downregulation, exon 1alpha methylation was analysed in a PCR-based assay. Of 49 tumours examined by immunostaining, 24 and 20 tumours expressed p16INK4a and p19ARF at nil to low levels, respectively. p19ARF was localized primarily to the nuclei of tumour cells, but was also seen to varying degrees in nuclei of lymphocytes, chondrocytes, fibroblasts, and epithelial cells. No tumour with normal p16INK4a had decreased p19ARF expression. Among 16 tumours with nil to low p16INK4a expression, 11 tumours exhibited full methylation of at least one site within exon 1alpha and these tumours showed normal p19ARF expression. In contrast, no methylation of exon 1alpha was observed in five tumours which also lacked p19ARF. In normal lung, p16INK4a and p19ARF were not expressed at detectable levels, the multiplex RT-PCR results were balanced, and sites within exon 1alpha were strongly methylated. In tumours, imbalanced multiplex RT-PCR data (p16INK4a
dc.language.isoenen
dc.subjectCancer DNAen
dc.subjectCancer Proteinsen
dc.subjectCancer RNAen
dc.subjectLung Canceren
dc.subjectCultured Tumour Cellsen
dc.subjectTumour Suppressor Protein p14ARFen
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAged
dc.subject.meshAnimals
dc.subject.meshCOS Cells
dc.subject.meshCarcinoma, Non-Small-Cell Lung
dc.subject.meshCyclin D1
dc.subject.meshCyclin-Dependent Kinase Inhibitor p16
dc.subject.meshDNA Methylation
dc.subject.meshDNA, Neoplasm
dc.subject.meshExons
dc.subject.meshFemale
dc.subject.meshG1 Phase
dc.subject.meshGene Expression Regulation, Neoplastic
dc.subject.meshGenes, Overlapping
dc.subject.meshGenes, Tumor Suppressor
dc.subject.meshGenes, p16
dc.subject.meshGenes, p53
dc.subject.meshHela Cells
dc.subject.meshHumans
dc.subject.meshK562 Cells
dc.subject.meshLung Neoplasms
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshNeoplasm Proteins
dc.subject.meshProteins
dc.subject.meshRNA, Messenger
dc.subject.meshRNA, Neoplasm
dc.subject.meshRetinoblastoma Protein
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction
dc.subject.meshTumor Cells, Cultured
dc.subject.meshTumor Suppressor Protein p14ARF
dc.subject.meshTumor Suppressor Protein p53
dc.titleExpression of p16INK4a/p16alpha and p19ARF/p16beta is frequently altered in non-small cell lung cancer and correlates with p53 overexpression.en
dc.typeArticleen
dc.contributor.departmentDepartment of Clinical Research, University of Bern, Switzerland.en
dc.identifier.journalOncogeneen
html.description.abstractThe CDKN2 locus expresses two different mRNA transcripts, designated alpha and beta. The protein product of the alpha transcript is the cell cycle inhibitor and tumour suppressor p16INK4a. The beta transcript is translated in an alternate reading frame (ARF) and in humans encodes a 15 kDa protein (p19ARF). Immunohistochemical and Western analysis of p16INK4a has shown that the protein is downregulated in a significant number of tumours, but less is known on the expression of the p19ARF. We have examined the expression of p16INK4a and p19ARF in resectable non-small cell lung cancer (NSCLC) by immunostaining (n=49) and multiplex RT-PCR (n=28). In order to investigate the mechanism responsible for p16INK4a downregulation, exon 1alpha methylation was analysed in a PCR-based assay. Of 49 tumours examined by immunostaining, 24 and 20 tumours expressed p16INK4a and p19ARF at nil to low levels, respectively. p19ARF was localized primarily to the nuclei of tumour cells, but was also seen to varying degrees in nuclei of lymphocytes, chondrocytes, fibroblasts, and epithelial cells. No tumour with normal p16INK4a had decreased p19ARF expression. Among 16 tumours with nil to low p16INK4a expression, 11 tumours exhibited full methylation of at least one site within exon 1alpha and these tumours showed normal p19ARF expression. In contrast, no methylation of exon 1alpha was observed in five tumours which also lacked p19ARF. In normal lung, p16INK4a and p19ARF were not expressed at detectable levels, the multiplex RT-PCR results were balanced, and sites within exon 1alpha were strongly methylated. In tumours, imbalanced multiplex RT-PCR data (p16INK4a<p19ARF) predicted methylation of exon 1alpha (P=0.0006) as well as downregulation of p16INK4a. p19ARF downregulation was inversely correlated with p53 overexpression (P=0.025), whilst negative immunostaining for p16INK4a was inversely correlated with pRb down-regulation (P=0.003) and directly correlated with p53 overexpression as assessed by immunostaining (P=0.015). Our results show that: (1) p16INK4a and p19ARF expression are altered in almost half of resectable NSCLC; (2) methylation within exon 1alpha is a frequent, but not the only mechanism of p16INK4a downregulation; and that (3) the inverse association of p19ARF and p53 alteration is consistent with a linked pathway.


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