Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling.
The genome of mantle cell lymphoma (MCL) is, in addition to the translocation t(11;14), characterized by a high number of secondary chromosomal gains and losses that probably account for the various survival times of MCL patients. We investigated 77 primary MCL tumors with available clinical information using high-resolution RNA expression and genomic profiling and applied our recently developed gene expression and dosage integrator algorithm to identify novel genes and pathways that may be of relevance for the pathobiology of MCL. We show that copy number neutral loss of heterozygosity is common in MCL and targets regions that are frequently affected by deletions. The molecular consequences of genomic copy number changes appear complex, even in genomic loci with identified tumor suppressors, such as the region 9p21 containing the CDKN2A locus. Moreover, the deregulation of novel genes, such as CUL4A, ING1, and MCPH1, may affect the 2 crucial pathogenetic mechanisms in MCL, the disturbance of the proliferation, and DNA damage response pathways. Deregulation of the Hippo pathway may have a pathogenetic role in MCL because decreased expression of its members MOBKL2A, MOBKL2B, and LATS2 was associated with inferior outcome, including an independent validation series of 32 MCLs.
Hartmann
Elena M
EM
Institute of Pathology, University of Wuerzburg, Josef-Schneider-Strasse 2, Wuerzburg, Germany.
Campo
Elias
E
Wright
George
G
Lenz
Georg
G
Salaverria
Itziar
I
Jares
Pedro
P
Xiao
Wenming
W
Braziel
Rita M
RM
Rimsza
Lisa M
LM
Chan
Wing-Chung
WC
Weisenburger
Dennis D
DD
Delabie
Jan
J
Jaffe
Elaine S
ES
Gascoyne
Randy D
RD
Dave
Sandeep S
SS
Mueller-Hermelink
Hans-Konrad
HK
Staudt
Louis M
LM
Ott
German
G
Beà
Sílvia
S
Rosenwald
Andreas
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006720:Homozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D019656:Loss of Heterozygosity / Q000235:genetics; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
C431903:MOB2 protein, human; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases