Expression of p16INK4a/p16alpha and p19ARF/p16beta is frequently altered in non-small cell lung cancer and correlates with p53 overexpression.

2.50
Hdl Handle:
http://hdl.handle.net/10541/92007
Title:
Expression of p16INK4a/p16alpha and p19ARF/p16beta is frequently altered in non-small cell lung cancer and correlates with p53 overexpression.
Authors:
Vonlanthen, S; Heighway, Jim; Tschan, M P; Borner, M M; Altermatt, H J; Kappeler, A; Tobler, A; Fey, M F; Thatcher, Nick; Yarbrough, W G; Betticher, Daniel C
Abstract:
The 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.
Affiliation:
Department of Clinical Research, University of Bern, Switzerland.
Citation:
Expression 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 Oncogene
Journal:
Oncogene
Issue Date:
26-Nov-1998
URI:
http://hdl.handle.net/10541/92007
DOI:
10.1038/sj.onc.1202501
PubMed ID:
9840942
Type:
Article
Language:
en
ISSN:
0950-9232
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorVonlanthen, Sen
dc.contributor.authorHeighway, Jimen
dc.contributor.authorTschan, M Pen
dc.contributor.authorBorner, M Men
dc.contributor.authorAltermatt, H Jen
dc.contributor.authorKappeler, Aen
dc.contributor.authorTobler, Aen
dc.contributor.authorFey, M Fen
dc.contributor.authorThatcher, Nicken
dc.contributor.authorYarbrough, W Gen
dc.contributor.authorBetticher, Daniel Cen
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<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.en
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

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