Prevalent hyper-methylation of the CDH13 gene promoter in malignant B cell lymphomas

CDH13 (H-cadherin) is a member of the cadherin superfamily, which plays an important role in cell recognition and adhesion. We examined the expression and methylation status of the CDH13 gene in diffuse large B cell lymphomas (B-DLCLs). We found decreased expression of the CDH13 gene in all of 6 hematopoietic cell lines by reverse transcription-polymerase chain reaction (RT-PCR). Promoter hyper-methylation of the gene was detected in all 6 cell lines and in 13 of 19 (68%) B-DLCL samples by methylation-specific PCR. Interestingly, the methylation frequency of the CDH13 gene was comparable to those of the tumor suppressor genes p15 (68%) and p16 (74%) detected in B-DLCLs. Sequencing of bisulfite-treated DNA revealed hyper-methylation of the CpG islands of the CDH13 promoter in B-DLCLs and the cell lines. Treatment with 5-aza-2'-deoxycytidine restored CDH13 gene expression in a cell line in which promoter hyper-methylation and impaired expression of the CDH13 gene were observed. Loss of heterozygosity (LOH) around the CDH13 gene on chromosome 16q24 was detected in 6 of 15 (40%) informative cases with microsatellite marker D16S507 and in 6 of 15 (40%) cases with D16S422 in B-DLCLs. In all of 4 B-DLCL cases which showed both promoter methylation and LOH at the two marker loci, expression of the CDH13 gene was significantly low. These results suggest that silencing of the CDH13 gene by aberrant promoter methylation and allelic deletion is associated with tumorigenesis in a subset of B-DLCL.