title: The molecular signature of mantle cell lymphoma reveals multiple signals favoring cell survival.
abstract: Mantle cell lymphoma (MCL) is a prototypical neoplastic disease in which a common cytogenetic alteration, t11;14, leading to cyclin D1 overexpression, is associated with other changes that need to be considered in an explanation of the clinical, morphological, and molecular variability of this disease. Using a cDNA microarray (Oncochip-CNIO) containing clones for 6386 cancer-related genes, we have analyzed the expression profiles of a series of 38 cases. After normalization with the expression profiling of sorted mantle zone lymphocytes, we have related the findings to conventional clinical and molecular variables, including immunoglobulin variable heavy chain somatic mutation, blastoid cytology, increased proliferation, and long-term survival. MCL signature (446 genes) includes genes involved in apoptosis, cell cycle, signal transduction, and cell structure. Especially striking was the presence of multiple concurrent alterations in the tumor necrosis factor and nuclear factor kappaB pathway, and the overexpression of IL10R and SPARC genes. We also identified a molecular signature for the presence of immunoglobulin variable heavy chain somatic mutation, which includes a number of genes potentially relevant in cancer (CDC14A, ras, and others). Signatures for proliferation and blastoid cytology were also found. An integrated analysis of these data yields a gene-expression based survival predictor (26 genes grouped into two clusters), which distinguishes half of the patients with a survival probability of 52% at 5 years. The predictive model has been confirmed by cross-validation. In conclusion, MCL seems to combine a disease-specific signature and different sets of genes of which the expression is associated with key clinical, molecular, and immunophenotypical events.
authors.affiliation: Molecular Pathology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Martínez
authors.forename: Francisca I
authors.initials: FI
authors.lastname: Camacho
authors.forename: Patrocinio
authors.initials: P
authors.lastname: Algara
authors.forename: Antonia
authors.initials: A
authors.lastname: Rodríguez
authors.forename: Ana
authors.initials: A
authors.lastname: Dopazo
authors.forename: Elena
authors.initials: E
authors.lastname: Ruíz-Ballesteros
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martínez-Climent
authors.forename: Javier
authors.initials: J
authors.lastname: García-Conde
authors.forename: Javier
authors.initials: J
authors.lastname: Menárguez
authors.forename: Fernando
authors.initials: F
authors.lastname: Solano
authors.forename: Manuela
authors.initials: M
authors.lastname: Mollejo
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002470:Cell Survival / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region