Letter to the Editor

Leukemia (2006) 20, 904–905. doi:10.1038/sj.leu.2404173; published online 2 March 2006

Partial uniparental disomy: a recurrent genetic mechanism alternative to chromosomal deletion in malignant lymphoma

I Nielaender1, J I Martín-Subero1, F Wagner2, J A Martínez-Climent3 and R Siebert1

  1. 1Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
  2. 2Deutsches Ressourcenzentrum für Genomforschung (RZPD), Berlin, Germany
  3. 3Center for Applied Medical Research CIMA, University of Navarra, Pamplona, Spain

Correspondence: R Siebert, E-mail: rsiebert@medgen.uni-kiel.de

Recent studies have highlighted the power of array-based comparative genomic hybridization (aCGH) to characterize chromosomal imbalances in mantle cell lymphoma (MCL).1, 2, 3 Several of the deletions detected in these studies, including losses in 1p, 8p, 9q, 9p, 13q and 17p, have been shown to correlate with prognosis.1, 2 It is widely assumed that chromosomal deletions exert their pathogenic effect through inactivation of tumor suppressor genes. However, novel reports have highlighted partial uniparental disomy (pUPD) as a frequent mechanism of tumor suppressor inactivation in acute leukemias and solid tumors.4, 5, 6 By loss of (part of) one parental chromosome and gain of the homologue from the other parent, pUPD results in loss of heterozygosity (LOH) without chromosomal deletion. As the gene dosage is not altered, pUPD cannot be detected by conventional cytogenetics, fluorescence in situ hybridization or aCGH. To investigate the role of this mechanism in MCL, we have performed genome-wide analyses of single nucleotide polymorphisms (SNPs) using a 100K SNP-array (GeneChip® Human Mapping 100K Set; Affymetrix, Santa Clara, CA, USA) in five t(11;14)-positive MCL cell lines (Granta-519, HBL-2, JEKO, REC-1 and UPN-1), which have been extensively studied by aCGH.2, 7 Copy number and LOH analyses were performed using the Chromosome Copy Number Analysis Tool (version, Affymetrix) applying a 0.5 Mb genome smoothing filter.

Partial UPD was defined as a region spanning at least 50 SNPs with homozygous allele calls and a –log10 (P-value) for LOH above 15 in the absence of a deletion.

A median number of 8 (range=5–20) pUPDs were identified in the samples, indicating that pUPD is a common phenomenon in MCL cell lines. Most interestingly, the regions of pUPD detected in the MCL cell lines affected regions of recurrent chromosomal deletion described in the aCGH studies (Figure 1).1, 2, 3 Furthermore, we found an excellent agreement between copy number changes detected by aCGH and SNP-array analyses.

Figure 1.
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Examples of partial uniparental disomy (pUPD) detected in mantle cell lymphoma cell lines. The profile of genomic imbalances is given as a black line with a value of 2 indicating a balanced status. The –log10 of P-values for loss of heterozygosity (LOH) are overlaid in gray, and those exceeding 15 were considered indicative of LOH (for a better display, larger values were cut at 20). Chromosomes are shown from pter (left) to qter (right). Regions meeting the defined criteria for pUPD are underlaid by black bars.

Full figure and legend (118K)

To study whether pUPD is common also in other types of lymphomas, we took advantage of the 10K SNP-array data publicly available from the Wellcome Trust Sanger Institute Cancer Genome Project (http://www.sanger.ac.uk/genetics/CGP). We focused on Burkitt lymphoma (BL) cell lines because this lymphoma shows a low number of chromosomal changes in addition to the pathogenetic Burkitt translocation t(8;14)(q24;q32) or its variants. Among others, we observed recurrent pUPD in 17p and 18q in BL cell lines. Chromosome 17p contains the TP53 tumor suppressor gene, whereas 18q harbors the candidate tumor suppressor NOXA, which is homozygously deleted in a BL cell line (Mestre et al., submitted).

In summary, these findings show pUPD to be recurrent in lymphoma and to affect regions commonly targeted by deletions. Further studies in primary tumor samples are mandatory to extend these findings, but problems of allele discrimination caused by contaminating non-neoplastic cells have to be resolved. If associating genetic findings with clinical outcome, pUPD has to be considered as a mechanism of tumor suppressor gene inactivation alternative to chromosomal deletion.



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  2. Rubio-Moscardo F, Climent J, Siebert R, Piris MA, Martin-Subero JI, Nielander I et al. Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome. Blood 2005; 105: 4445–4454. | Article | PubMed | ISI | ChemPort |
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  6. Teh MT, Blaydon D, Chaplin T, Foot NJ, Skoulakis S, Raghavan M et al. Genomewide single nucleotide polymorphism microarray mapping in basal cell carcinomas unveils uniparental disomy as a key somatic event. Cancer Res 2005; 65: 8597–8603. | Article | PubMed | ISI | ChemPort |
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This study was supported by the Lymphoma Research Foundation (New York). We thank Dr Ali Turhan for allowing to use the UPN-1 cell line. LOH data from BL cell lines were obtained from the Wellcome Trust Sanger Institute Cancer Genome Project website, http://www.sanger.ac.uk/genetics/CGP