title: Quantitative gene expression deregulation in mantle-cell lymphoma: correlation with clinical and biologic factors.
abstract: OBJECTIVE
  There is evidence for a direct role of quantitative gene expression deregulation in mantle-cell lymphoma (MCL) pathogenesis. Our aim was to investigate gene expression associations with other pathogenic factors and the significance of gene expression in a multivariate survival analysis.
  
  
  METHODS
  Quantitative expression of 20 genes of potential relevance for MCL prognosis and pathogenesis were analyzed using real-time reverse transcriptase polymerase chain reaction and correlated with clinical and genetic factors, tumor morphology, and Ki-67 index in 65 MCL samples.
  
  
  RESULTS
  Genomic losses at the loci of TP53, RB1, and P16 were associated with reduced transcript levels of the respective genes, indicating a gene-dosage effect as the pathomechanism. Analysis of gene expression correlations between the candidate genes revealed a separation into two clusters, one dominated by proliferation activators, another by proliferation inhibitors and regulators of apoptosis. Whereas only weak associations were identified between gene expression and clinical parameters or blastoid morphology, several genes were correlated closely with the Ki-67 index, including the short CCND1 variant (positive correlation) and RB1, ATM, P27, and BMI (negative correlation). In multivariate survival analysis, expression levels of MYC, MDM2, EZH2, and CCND1 were the strongest prognostic factors independently of tumor proliferation and clinical factors.
  
  
  CONCLUSIONS
  These results indicate a pathogenic contribution of several gene transcript levels to the biology and clinical course of MCL. Genes can be differentiated into factors contributing to proliferation deregulation, either by enhancement or loss of inhibition, and proliferation-independent factors potentially contributing to MCL pathogenesis by apoptosis impairment.
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Kienle
authors.forename: Tiemo
authors.initials: T
authors.lastname: Katzenberger
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Doreen
authors.initials: D
authors.lastname: Saupe
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Holger
authors.initials: H
authors.lastname: Kohlhammer
authors.forename: Thomas F E
authors.initials: TF
authors.lastname: Barth
authors.forename: Sylvia
authors.initials: S
authors.lastname: Höller
authors.forename: Jörg
authors.initials: J
authors.lastname: Kalla
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Hans Konrad
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016896:Treatment Outcome
chemical_list: D019394:Ki-67 Antigen