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概要

Fine Mapping of the 15q21 Region Implicates TP53BP1 and B2M in the Lymphomagenesis of Follicular and Diffuse Large B-Cell Lymphomas

Aya-Bonilla Carlos, Camilleri Emily, Benton Miles, Haupt Larisa M, Marlton Paula, Lea Rod A, Gandhi Maher K and Griffiths Lyn R

Background and aim: Recent studies focusing on the discovery of common alterations across cases suffering from follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) have reported loss of heterozygosity (LOH) and deletions events targeting the 15q21 region, indicating the relevance of this region in the lymphomagenesis of FL and DLBCL. Herein, we investigated the genetic structure of this region by studying identified LOH and copy-loss events and examined this region in the lymphomagenesis of FL and DLBCL. Methods: Fine mapping of the genomic region between the 15q15.1 and 15q21.1 loci was performed using data from copy number variation (CNV) and high resolution LOH analyses of FL (n=21) and DLBCL (n=21) cases. Validation of LOH of this region was performed using microsatellites followed by quantitative-PCR (qPCR) to measure the transcriptional abundance of TP53BP1 and B2M. Also, direct sequencing of exons 1 and 2 of B2M was performed on tumor DNA from 24 FL and 23 DLBCL samples. Results: The integration of LOH and CNV data identified copy-loss alterations at the 15q21 loci spanning a 7.5 Mb region, covering two LOH regions, termed LOH-1 and LOH-2. The LOH-1 region spans 3.4 Mb and contains 53 genes, from which TP53BP1 (tumor-protein-p53-binding-protein-1) and B2M (Beta-2-Microglobulin) were identified as the most likely target genes due to their roles in DNA double strand break (DSB) repair and immune recognition, respectively. Expression analyses revealed a significant up-regulation of TP53BP1 in NHL with LOH, but no significant changes in B2M expression were observed. Direct sequencing of exons 1 and 2 in B2M in FL and DLBCL identified two monoallelic microdeletions associated with DLBCL. Conclusion: This study identified that deletion mapping to the 15q21 locus cover two LOH regions. LOH of the TP53BP1 and B2M genes appear to be common alterations in FL and DLBCL tumorigenesis.