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

Author:

Hartmann Elena M.1,Campo Elias2,Wright George3,Lenz Georg4,Salaverria Itziar25,Jares Pedro2,Xiao Wenming6,Braziel Rita M.7,Rimsza Lisa M.8,Chan Wing-Chung9,Weisenburger Dennis D.9,Delabie Jan10,Jaffe Elaine S.11,Gascoyne Randy D.12,Dave Sandeep S.13,Mueller-Hermelink Hans-Konrad1,Staudt Louis M.14,Ott German15,Beà Sílvia2,Rosenwald Andreas1

Affiliation:

1. Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany;

2. Department of Pathology, University of Barcelona, Hospital Clinic, Barcelona, Spain;

3. Biometric Research Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD;

4. Department of Hematology, Oncology and Tumor Immunology, Charite Universitätsmedizin Berlin, Berlin, Germany;

5. Institute of Human Genetics, Christian-Albrechts University, Kiel, Germany;

6. Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, NIH, Bethesda, MD;

7. Southwest Oncology Group, Oregon Health & Science University, Portland;

8. Department of Pathology, University of Arizona, Tucson;

9. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha;

10. Norwegian Radium Hospital, Oslo, Norway;

11. Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD;

12. British Columbia Cancer Agency, Vancouver, BC;

13. Department of Medicine, Duke University Medical Center, Durham, NC;

14. Metabolism Branch, National Cancer Institute, NIH, Bethesda, MD; and

15. Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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