Constitutional and somatic deletions of the Williams-Beuren syndrome critical region in Non-Hodgkin Lymphoma
© Guenat et al.; licensee BioMed Central Ltd. 2014
Received: 25 August 2014
Accepted: 20 October 2014
Published: 7 November 2014
Here, we report and investigate the genomic alterations of two novel cases of Non-Hodgkin Lymphoma (NHL) in children with Williams-Beuren syndrome (WBS), a multisystem disorder caused by 7q11.23 hemizygous deletion. Additionally, we report the case of a child with NHL and a somatic 7q11.23 deletion. Although the WBS critical region has not yet been identified as a susceptibility locus in NHL, it harbors a number of genes involved in DNA repair. The high proportion of pediatric NHL reported in WBS is intriguing. Therefore, the role of haploinsufficiency of genes located at 7q11.23 in lymphomagenesis deserves to be investigated.
List of pediatric cancers reported in WBS patients
Date of publication
Age (years), gender
Type of tumor
WBS Patient 1
WBS Patient 2
NHL (B-NHL stage IV)
NHL (Burkitt) and Ewing sarcoma
Urisarri Ruiz A
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. 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 ; 3) RFC2 encodes a subunit of the Replication Factor C complex that interacts with BRCA1 for post replication repair after UV-induced DNA damage ; 4) GTF2I encodes a transcription factor that promotes DNA translesion synthesis and genomic stability interacting with PCNA and DNA polymerases . 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 .
7q11.23 deletion has been found as a relatively common occurrence in pilocytic astrocytoma , of which variants have been reported in 2 patients with WBS ,. 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 . 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 . Amplifications of the WBS critical region have also been found in a variety of cancers including large B-cell lymphoma , ovarian adenocarcinoma , papillary thyroid carcinoma  and cholangiocarcinoma . 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.
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.
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