title: CDK4 is a probable target gene in a novel amplicon at 12q13.3-q14.1 in lung cancer.
abstract: Several chromosomal regions are recurrently amplified or deleted in lung tumors, but little is known about the underlying genes, which could be important mediators in tumor formation or progression. In lung cancer, the RB1-CCND1-CDKN2A pathway, involved in the G1-S transition, is damaged in nearly all tumors. In the present study, we localized a novel amplicon in lung tumors to a fragment of less than 0.5 Mb at 12q13.3-q14.1 by using comparative genomic hybridization (CGH) on cDNA microarrays. This approach enabled us to identify 10-15 genes with the most consistent amplifications. Semiquantitative RT-PCR analyses of 13 genes in this region showed that four of them (CDK4, CYP27B1, METTL1, and TSFM) were also highly up-regulated. Immunohistochemical (IHC) analysis of 141 tumor samples on a tissue microarray showed that CDK4 was expressed at a high level in 23% of lung tumors. Six (21.4%) of the tumors with high CDK4 expression (n = 28) were shown by fluorescence in situ hybridization (FISH) to contain the 12q13.3-q14.1 amplification. For CDK4, a positive correlation was found between gene copy number (FISH and CGH array), mRNA expression (RT-PCR), and level of protein expression (IHC). CDK4 expression did not correlate with CDKN2A methylation status. Amplification of CDK4 has been described in other tumor types, but its role in lung cancer remains to be elucidated. Although CDK4 amplification seems to be a relatively rare event (4.3%) in lung tumors, it indicates the significance of the RB1-CCND1 pathway in lung tumorigenesis.
authors.affiliation: Department of Occupational Medicine, Finnish Institute of Occupational Health, Helsinki, Finland. harriet.wikman@helsinki.fi
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
authors.forename: Penny
authors.initials: P
authors.lastname: Nymark
authors.forename: Aki
authors.initials: A
authors.lastname: Väyrynen
authors.forename: Sonata
authors.initials: S
authors.lastname: Jarmalaite
authors.forename: Anne
authors.initials: A
authors.lastname: Kallioniemi
authors.forename: Kaisa
authors.initials: K
authors.lastname: Salmenkivi
authors.forename: Katri
authors.initials: K
authors.lastname: Vainio-Siukola
authors.forename: Kirsti
authors.initials: K
authors.lastname: Husgafvel-Pursiainen
authors.forename: Sakari
authors.initials: S
authors.lastname: Knuutila
authors.forename: Maija
authors.initials: M
authors.lastname: Wolf
authors.forename: Sisko
authors.initials: S
authors.lastname: Anttila
mesh_terms: D002874:Chromosome Mapping / Q000379:methods; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005784:Gene Amplification / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D046228:Microarray Analysis / Q000379:methods; D009693:Nucleic Acid Hybridization / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases