Quantitative gene expression deregulation in mantle-cell lymphoma: correlation with clinical and biologic factors.
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.
Kienle
Dirk
D
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Katzenberger
Tiemo
T
Ott
German
G
Saupe
Doreen
D
Benner
Axel
A
Kohlhammer
Holger
H
Barth
Thomas F E
TF
Höller
Sylvia
S
Kalla
Jörg
J
Rosenwald
Andreas
A
Müller-Hermelink
Hans Konrad
HK
Möller
Peter
P
Lichter
Peter
P
Döhner
Hartmut
H
Stilgenbauer
Stephan
S
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
D019394:Ki-67 Antigen