title: Uniparental disomies, homozygous deletions, amplifications, and target genes in mantle cell lymphoma revealed by integrative high-resolution whole-genome profiling.
abstract: Mantle cell lymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation and a high number of secondary chromosomal alterations. However, only a limited number of target genes have been identified. We have studied 10 MCL cell lines and 28 primary tumors with a combination of a high-density single-nucleotide polymorphism array and gene expression profiling. We detected highly altered genomes in the majority of the samples with a high number of partial uniparental disomies (UPDs). The UPD at 17p was one of the most common, and it was associated with TP53 gene inactivation. Homozygous deletions targeted 4 known tumor suppressor genes (CDKN2C, BCL2L11, CDKN2A, and RB1) and 6 new genes (FAF1, MAP2, SP100, MOBKL2B, ZNF280A, and PRAME). Gene amplification coupled with overexpression was identified in 35 different regions. The most recurrent amplified regions were 11q13.3-q13.5, 13q31.3, and 18q21.33, which targeted CCND1, C13orf25, and BCL2, respectively. Interestingly, the breakpoints flanking all the genomic alterations, including UPDs, were significantly associated with genomic regions enriched in copy number variants and segmental duplications, suggesting that the recombination at these regions may play a role in the genomic instability of MCL. This integrative genomic analysis has revealed target genes that may be potentially relevant in MCL pathogenesis.
authors.affiliation: Hematopathology Unit, Department of Pathology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Beà
authors.forename: Itziar
authors.initials: I
authors.lastname: Salaverria
authors.forename: Lluís
authors.initials: L
authors.lastname: Armengol
authors.forename: Magda
authors.initials: M
authors.lastname: Pinyol
authors.forename: Verónica
authors.initials: V
authors.lastname: Fernández
authors.forename: Elena M
authors.initials: EM
authors.lastname: Hartmann
authors.forename: Pedro
authors.initials: P
authors.lastname: Jares
authors.forename: Virginia
authors.initials: V
authors.lastname: Amador
authors.forename: Luís
authors.initials: L
authors.lastname: Hernández
authors.forename: Alba
authors.initials: A
authors.lastname: Navarro
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
mesh_terms: D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17; D005784:Gene Amplification; D018628:Gene Dosage; D052138:Genes, Neoplasm / Q000502:physiology; D055106:Genome-Wide Association Study / Q000379:methods*; D006720:Homozygote; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D020522:Lymphoma, Mantle-Cell / Q000175:diagnosis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D024182:Uniparental Disomy / Q000175:diagnosis* / Q000235:genetics