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01.12.2014 | Letter to the Editor | Ausgabe 1/2014 Open Access

Journal of Hematology & Oncology 1/2014

Constitutional and somatic deletions of the Williams-Beuren syndrome critical region in Non-Hodgkin Lymphoma

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2014
Autoren:
David Guenat, Samuel Quentin, Carmelo Rizzari, Catarina Lundin, Tiziana Coliva, Patrick Edery, Helen Fryssira, Laurent Bermont, Christophe Ferrand, Jean Soulier, Christophe Borg, Pierre-Simon Rohrlich
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13045-014-0082-4) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contribution

DG, JS, PSR and CB designed the study. SQ and JS performed CGH-array and analyzed the results. DG, and CF analyzed the next-generation sequencing data. LB performed Microsatellite instability assay. CR, TC, PSR, CL, HF and PE provided clinical and diagnostic input. DG, PSR, CL, CB and CR wrote the manuscript. All authors read, reviewed and approved the manuscript.

Findings

Chromosomal disorders are common circumstances for the discovery of a genetic predisposition to cancer allowing identification and localization of new oncogenes. Williams-Beuren syndrome (WBS) is a multisystem disorder caused by 7q11.23 hemizygous microdeletion [1]. WBS is not currently considered as a risk factor for cancer. However, the low incidence of both WBS and pediatric NHL (Non-Hodgkin Lymphoma) might hamper our ability to identify any association between these rare diseases. An increased risk of NHL in WBS might have easily been underestimated until today. Furthermore, the number of pediatric cancer reported in WBS has reached 11 cases and, strikingly, 8 (73%) of them where NHL, mostly Burkitt lymphoma (Table 1). Here, we report 2 novel cases of NHL in children with WBS and the additional case of a non-WBS child with NHL and somatic 7q11.23 deletion (see case description in Additional file 1).
Table 1
List of pediatric cancers reported in WBS patients
 
Study Samples
Authors
Date of publication
Age (years), gender
Type of tumor
Reference
1
WBS Patient 1
Guenat D
TS
7, F
NHL (Burkitt)
-
2
WBS Patient 2
Guenat D
TS
10, M
NHL (B-NHL stage IV)
-
3
-
Vanhapiha N
2014
7, M
NHL (Burkitt) and Ewing sarcoma
[2]
4
-
Chonan M
2013
3, M
Astrocytoma
[3]
5
-
Zhukova N
2013
8, M
NHL (Burkitt)
[4]
6
-
Onimoe G
2011
10, F
NHL (Burkitt)
[5]
7
-
Urisarri Ruiz A
2008
12, M
NHL (T-cell)
[6]
8
-
Thornburg CD
2005
1,?
NHL (Burkitt)
[7]
9
-
Amenta S
2004
8, M
NHL (Burkitt)
[8]
10
-
Culic V
2002
14, M
ALL
[9]
11
-
Semmekrot BA
1985
5, ?
Astrocytoma
[10]
TS: This Study; NHL: Non-Hodgkin Lymphoma; ALL: Acute Lymphoblastic Leukemia, F: female; M: male.
Since several different deletions account for the genotype of WBS, we first investigated germline and somatic structural variants in these latest 3 patients using array-based CGH (Figure 1). We confirmed the presence of a constitutional 7q11.23 deletion in WBS patients. No germline Copy Number Variation (CNV) was observed in patient 3. Intriguingly, the somatically acquired 7q11.23 deletion that occurred in lymphoma of patient 3 was similar to the classical germline deletion observed in WBS patients and there was no evidence of other rearrangements occurred in this tumor. Lymphoma cells of WBS patients exhibited CNV commonly found in B cell lymphoma excepting a subclonal deletion of approximately 10 Mb at the locus 2q33.1-q35 involving IKZF2 in WBS patient 2. A recent study by Holmfeldt et al. demonstrated that this deletion was common in low-hypodiploid acute lymphoblastic leukemia [11] but this deletion had never been described in NHL. Then, next generation sequencing of the WBS region showed a germline homozygous variant in exon 25 of ELN (c.1741G > C, p.Gly581Arg, rs.17855988) in the 2 WBS patients. ELN encodes elastin, a constituent of elastic fibers. Many variants of ELN has been described and were associated to the severity of cardiovascular symptoms of WBS patients. No recurrent variant was observed in the 27 other genes nor in the 2 miRNA loci of the WBS critical region.
A number of genes mapping to the WBS region are involved in DNA repair: 1) Eleven PMS2 pseudogenes loci are located at 7q11.23. PMS2 plays a crucial role in the DNA Mismatch Repair and a childhood cancer syndrome is associated to biallelic mutations of PMS2[12]. However, in our study the 3 patients showed stable microsatellites (Additional file 2); 2) BAZ1B encodes a transcription factor with an intrinsic tyrosine kinase domain that phosphorylates Tyr142 of histone H2A.X and is involved in the maintaining of gH2A.X in the sites of DNA damages [13]; 3) RFC2 encodes a subunit of the Replication Factor C complex that interacts with BRCA1 for post replication repair after UV-induced DNA damage [14]; 4) GTF2I encodes a transcription factor that promotes DNA translesion synthesis and genomic stability interacting with PCNA and DNA polymerases [15]. Finally, the hypothesis of a constitutional genomic instability in WBS is consistent with the results of a study by Savina et al. that showed experimentally the relationship between an abnormal DNA-damage response and the 7q11.23 hemizygous microdeletion when comparing the comet assay data in FISH-positive and FISH-negative lymphocytes from WBS-suspected patients [16].
7q11.23 deletion has been found as a relatively common occurrence in pilocytic astrocytoma [17], of which variants have been reported in 2 patients with WBS [3],[10]. Nevertheless, genome-wide copy number analysis in NHL, including a recent study by Conde et al. that analyzed 648 patients, ages 20 to 85 years, have not found a susceptibility locus at 7q11.23 [18]. However, NHL in adults encompasses a heterogeneous spectrum of diseases in which diffuse large B-cell lymphoma predominates. NHL in children is a more rare event and pediatric DLBCL is uncommon. Burkitt lymphoma that predominates in pediatric NHL, has also been studied by genome-wide CNV studies. Notably, Scholtysik et al. demonstrated a recurrent loss at 7q11.22, localized at the centromeric limit of the WBS critical region, in 39 cases of BL [19]. Amplifications of the WBS critical region have also been found in a variety of cancers including large B-cell lymphoma [20], ovarian adenocarcinoma [21], papillary thyroid carcinoma [22] and cholangiocarcinoma [23]. This might reflect complex mechanisms that regulate initiation/promotion of cancer cells by oncogenes and tumor suppressor genes clustered around recombination hot spots or fragile sites in the WBS region.
Althought no epidemiological studies demonstrated an increased risk of cancer in WBS the high proportion of pediatric NHL reported in WBS and the occurrence of a somatic deletion of 7q11.23 in NHL is intriguing. In these patients, NHL seems to arise in the presence of the typical WBS microdeletion and in the absence of homozygous mutation. The role of haploinsufficiency of genes located at 7q11.23 in lymphomagenesis deserves to be investigated.

Additional files

Acknowledgments

This work was funded by the French association “Cent pour sang la vie”. We would like to acknowledge the study participants and their parents. We thank Brigitte Gilbert-Dussardier for her help in contacting the different investigators. We also thank “Comitato Maria Letizia Verga (Monza) per lo studio e la cura della leucemia infantile” for the continuous support to research activities of Carmelo Rizzari and Tiziana Coliva and “The Swedish Childhood Cancer Foundation” for financial support to research works of Catarina Lundin. Finally, we thank Annalisa Weygandt for the English language editing of the manuscript.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​4.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.

Competing interests

The authors declare that they have no competing interests.

Authors’ contribution

DG, JS, PSR and CB designed the study. SQ and JS performed CGH-array and analyzed the results. DG, and CF analyzed the next-generation sequencing data. LB performed Microsatellite instability assay. CR, TC, PSR, CL, HF and PE provided clinical and diagnostic input. DG, PSR, CL, CB and CR wrote the manuscript. All authors read, reviewed and approved the manuscript.

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Zusatzmaterial
Additional file 2: Study of microsatellites instability by capillary electrophoresis fragment analysis. All patients have stables microsatellites in both normal and tumor DNA when compared with the Microsatellite Instable positive control (Control MSI+). BL: Burkitt Lymphoma, PBMC: Peripheral Blood Mononuclear Cells. (PNG 169 KB)
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Authors’ original file for figure 1
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