Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling

Elena M. Hartmann, Elias Campo, George Wright, Georg Lenz, Itziar Salaverria, Pedro Jares, Wenming Xiao, Rita M. Braziel, Lisa M Rimsza, Wing Chung Chan, Dennis D. Weisenburger, Jan Delabie, Elaine S. Jaffe, Randy D. Gascoyne, Sandeep S. Dave, Hans Konrad Mueller-Hermelink, Louis M. Staudt, German Ott, Sílvia Beà, Andreas Rosenwald

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)953-961
Number of pages9
JournalBlood
Volume116
Issue number6
DOIs
StatePublished - Aug 12 2010

Fingerprint

Mantle-Cell Lymphoma
Gene Dosage
Gene expression
Deregulation
Genes
Gene Expression
Tumors
RNA
DNA
Loss of Heterozygosity
DNA Damage
Neoplasms
Genome
Survival

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Hartmann, E. M., Campo, E., Wright, G., Lenz, G., Salaverria, I., Jares, P., ... Rosenwald, A. (2010). Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling. Blood, 116(6), 953-961. https://doi.org/10.1182/blood-2010-01-263806

Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling. / Hartmann, Elena M.; Campo, Elias; Wright, George; Lenz, Georg; Salaverria, Itziar; Jares, Pedro; Xiao, Wenming; Braziel, Rita M.; Rimsza, Lisa M; Chan, Wing Chung; Weisenburger, Dennis D.; Delabie, Jan; Jaffe, Elaine S.; Gascoyne, Randy D.; Dave, Sandeep S.; Mueller-Hermelink, Hans Konrad; Staudt, Louis M.; Ott, German; Beà, Sílvia; Rosenwald, Andreas.

In: Blood, Vol. 116, No. 6, 12.08.2010, p. 953-961.

Research output: Contribution to journalArticle

Hartmann, EM, Campo, E, Wright, G, Lenz, G, Salaverria, I, Jares, P, Xiao, W, Braziel, RM, Rimsza, LM, Chan, WC, Weisenburger, DD, Delabie, J, Jaffe, ES, Gascoyne, RD, Dave, SS, Mueller-Hermelink, HK, Staudt, LM, Ott, G, Beà, S & Rosenwald, A 2010, 'Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling', Blood, vol. 116, no. 6, pp. 953-961. https://doi.org/10.1182/blood-2010-01-263806
Hartmann, Elena M. ; Campo, Elias ; Wright, George ; Lenz, Georg ; Salaverria, Itziar ; Jares, Pedro ; Xiao, Wenming ; Braziel, Rita M. ; Rimsza, Lisa M ; Chan, Wing Chung ; Weisenburger, Dennis D. ; Delabie, Jan ; Jaffe, Elaine S. ; Gascoyne, Randy D. ; Dave, Sandeep S. ; Mueller-Hermelink, Hans Konrad ; Staudt, Louis M. ; Ott, German ; Beà, Sílvia ; Rosenwald, Andreas. / Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling. In: Blood. 2010 ; Vol. 116, No. 6. pp. 953-961.
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abstract = "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.",
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