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dc.contributor.authorBetticher, Daniel C
dc.contributor.authorWhite, Gavin R M
dc.contributor.authorVonlanthen, S
dc.contributor.authorLiu, X
dc.contributor.authorKappeler, A
dc.contributor.authorAltermatt, H J
dc.contributor.authorThatcher, Nick
dc.contributor.authorHeighway, Jim
dc.date.accessioned2010-03-23T16:25:46Z
dc.date.available2010-03-23T16:25:46Z
dc.date.issued1997-10-21
dc.identifier.citationG1 control gene status is frequently altered in resectable non-small cell lung cancer. 1997, 74 (5):556-62 Int. J. Canceren
dc.identifier.issn0020-7136
dc.identifier.pmid9355981
dc.identifier.urihttp://hdl.handle.net/10541/94726
dc.description.abstractProgression through the mammalian cell cycle is controlled by a series of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors. Cyclin D1, cdk4 and the tumour suppressors p16 and retinoblastoma protein (pRb) are thought to comprise a linked system governing cell passage through the G1 phase of the cell cycle. Extending an earlier study on cyclin D1 expression, a series of resectable non-small cell lung carcinomas (NSCLCs) was examined for defects in other elements of this control system. Forty-six of fifty-one NSCLC specimens exhibited at least one alteration of these cell-cycle regulators. Immunohistochemical analysis revealed that 33% and 47% of the tumours failed to express pRb and p16, respectively. Failure to detect pRb did not correlate with loss of heterozygosity at the RB1 locus. Eleven of 12 tumours showing positive (normal) pRb staining over-expressed nuclear localised cyclin D1, including 8 with amplification of the cyclin D1 gene (CCNDI). However, in a number of lesions (n = 5) where cyclin D1 was over-expressed but localised to the cytoplasm, pRb expression was undetectable. Sequencing of exons 1 and 2 of the p16 gene (CDKN2) revealed 3/51 tumours with somatic mutations (in addition to 1 case with a germ-line alteration). All of these lesions were positive for p16 protein. No clear homozygous deletions of CDKN2 were observed by multiplex PCR. As assessed by immunostaining using a p16 monoclonal antibody, there was an inverse correlation of pRb and p16 down-regulation. Whilst patients with tumours over-expressing cyclin D1 had a significantly lower incidence of local relapse, the group whose tumours failed to express pRb had a significantly greater risk of local relapse and tended to have shortened event-free survival. Our data show that alteration of at least one cell cycle-regulator gene occurs in the majority of resectable NSCLCs.
dc.language.isoenen
dc.subjectLung Canceren
dc.subject.meshAged
dc.subject.meshCarcinoma, Non-Small-Cell Lung
dc.subject.meshDNA Methylation
dc.subject.meshDown-Regulation
dc.subject.meshExons
dc.subject.meshFemale
dc.subject.meshG1 Phase
dc.subject.meshGene Expression Regulation, Neoplastic
dc.subject.meshGenes, Retinoblastoma
dc.subject.meshGenes, p16
dc.subject.meshHumans
dc.subject.meshLoss of Heterozygosity
dc.subject.meshLung Neoplasms
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshMutation
dc.subject.meshPolymerase Chain Reaction
dc.subject.meshRetinoblastoma Protein
dc.titleG1 control gene status is frequently altered in resectable non-small cell lung cancer.en
dc.typeArticleen
dc.contributor.departmentInstitute of Medical Oncology, Inselspital, University of Bern, Switzerland.en
dc.identifier.journalInternational Journal of Cancer.en
html.description.abstractProgression through the mammalian cell cycle is controlled by a series of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors. Cyclin D1, cdk4 and the tumour suppressors p16 and retinoblastoma protein (pRb) are thought to comprise a linked system governing cell passage through the G1 phase of the cell cycle. Extending an earlier study on cyclin D1 expression, a series of resectable non-small cell lung carcinomas (NSCLCs) was examined for defects in other elements of this control system. Forty-six of fifty-one NSCLC specimens exhibited at least one alteration of these cell-cycle regulators. Immunohistochemical analysis revealed that 33% and 47% of the tumours failed to express pRb and p16, respectively. Failure to detect pRb did not correlate with loss of heterozygosity at the RB1 locus. Eleven of 12 tumours showing positive (normal) pRb staining over-expressed nuclear localised cyclin D1, including 8 with amplification of the cyclin D1 gene (CCNDI). However, in a number of lesions (n = 5) where cyclin D1 was over-expressed but localised to the cytoplasm, pRb expression was undetectable. Sequencing of exons 1 and 2 of the p16 gene (CDKN2) revealed 3/51 tumours with somatic mutations (in addition to 1 case with a germ-line alteration). All of these lesions were positive for p16 protein. No clear homozygous deletions of CDKN2 were observed by multiplex PCR. As assessed by immunostaining using a p16 monoclonal antibody, there was an inverse correlation of pRb and p16 down-regulation. Whilst patients with tumours over-expressing cyclin D1 had a significantly lower incidence of local relapse, the group whose tumours failed to express pRb had a significantly greater risk of local relapse and tended to have shortened event-free survival. Our data show that alteration of at least one cell cycle-regulator gene occurs in the majority of resectable NSCLCs.


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