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. 2009 Mar 26;113(13):3059-69.
doi: 10.1182/blood-2008-07-170183. Epub 2008 Nov 4.

Uniparental disomies, homozygous deletions, amplifications, and target genes in mantle cell lymphoma revealed by integrative high-resolution whole-genome profiling

Sílvia Beà  1 , Itziar Salaverria, Lluís Armengol, Magda Pinyol, Verónica Fernández, Elena M Hartmann, Pedro Jares, Virginia Amador, Luís Hernández, Alba Navarro, German Ott, Andreas Rosenwald, Xavier Estivill, Elias Campo
Affiliations

Uniparental disomies, homozygous deletions, amplifications, and target genes in mantle cell lymphoma revealed by integrative high-resolution whole-genome profiling

Sílvia Beà et al. Blood. .

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.

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Figures

Figure 1
Figure 1
Uniparental disomy and uniparental trisomy in MCL. (A) Ideogram of the distribution of the UPD/UPT regions detected by SNP arrays. UPD/UPTs are represented on the left side of each chromosome; thin bars represent UPD regions, whereas thick bars represent gained/amplified regions with LOH (UPT). UPD/UPTs detected in the 10 cell lines are indicated in green, whereas UPD/UPTs detected in the primary MCL samples are indicated in blue. Acquired UPDs detected only in tumor cells were indicated in orange. The more recurrent overlapping regions were shaded in gray. (B) Chromosome 9 total/partial UPDs and homozygous deletions detected in MCL cell lines. Chromosome 9 profile is represented from pter (left) to qter (right). For each cell line, the top panel represents copy number alteration (genome smooth analysis [GSA], P value) and the bottom panel represents LOH (−log10 LOH P value). Regions with genomic losses and concomitant LOH are underlined with thick red bars, homozygous deletions (HD) are indicated with dark red squares, and regions with UPD are underlined with thick black bars. MINO showed a whole chromosome 9 UPD, whereas the 3 remaining cell lines showed a 9q UPD and concomitant loss of 9pter-p21. REC1 and MAVER1 showed homozygous deletions of CDKN2A gene at 9p21.3, and MAVER1 had 2 additional homozygous deletions (indicated by asterisks; Table 1).
Figure 2
Figure 2
Homozygous deletions in MCL cell lines detected by SNP array and qPCR. (A) Profiles of chromosomes 1 and 2 detected by the SNP array in 3 MCL cell lines, represented from pter (left) to qter (right). GSA P values represent copy number alterations. The lowest values (vertical red lines) pointed by arrows highlight regions with homozygous deletions and candidate genes. UPN1 showed a novel homozygous deletion including FAF1 gene at 1p32.3, whereas JEKO1 and MINO showed 2 concomitant homozygous deletions at 2q12.1 and 2q37, targeting BCL2L11 and SP100 genes, respectively. In addition, JEKO1 showed 2p gain and MINO gain of whole chromosome 2. (B) Representation of FAF1 and SP100 gene qPCR validation. For each gene, the copy number alteration (upper panel SNP array and lower panel qPCR) and expression values (top panel expression array and bottom panel qRT-PCR) are shown. The color codes for the DNA analysis represent the copy number changes and show a high concordance between the results of the respective techniques. Similarly, the relative mRNA expression levels are represented in a color scale (from green to red, indicating low to high expression, respectively) and also show a high concordance of the results. The genes included in the homozygous deleted regions (FAF1 in UPN1 and SP100 in JEKO1 and MINO) had undetectable mRNA levels supporting their inactivation in these MCL cell lines.
Figure 3
Figure 3
BCL2 and CCND1 gene amplifications in MCL confirmed by FISH analysis. FISH of representative metaphases with BCL2 (red), IGH (green), CCND1 (orange), and CEP11 (green) specific probes. (A) The HBL2 cell line shows a tandem high-copy number BCL2 amplification (red arrow). (B) The BCL2 locus is amplified in a primary MCL (red signals) from the validation set that also showed a 18q21 amplification by CGH. (C) The HBL2 cell line has an amplified CCND1-IGH rearrangement (red arrow) and 2 nontranslocated chromosomes 11 with CCND1 signal (red) below the centromere of chromosome 11 (green). The CCND1-IGH amplified fusion was confirmed by a dual-color dual-fusion probe (data not shown). (D) The MAVER1 cell line has 2 high-level tandem amplifications of CCND1 (red arrows) in 2 different chromosomes: one corresponds to the complex t(11;14) translocation in chromosome 6. The chromosome carrying the second amplified region has not been identified. A nontranslocated chromosome 11 with the red CCND1 signal associated with the green centromere 11 probe is also observed.
Figure 4
Figure 4
Representative examples of the enrichment of CNVs and segmental duplications in MCL breakpoints. Association of MCL chromosomal breakpoints in CNV/SDs loci based on computational simulations that compared the expected number of breakpoints containing CNV/SDs with the observed number in MCL cell lines and primary tumors. A significant enrichment of breakpoints in CNV loci was found for UPDs/UPTs (A) and chromosomal losses (B). Similarly, a significant enrichment of breakpoints in SD loci was found for losses (C), whereas breakpoints of chromosomal gains have no association with SDs (D).
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