β 2 ‐microglobulin aberrations in diffuse large B‐cell lymphoma of the testis and the central nervous system

Human leukocyte antigen (HLA) class I molecules are expressed on the surface of all nucleated cells and present antigenic peptides to cytotoxic T cells, thereby playing an important role in initiating the cellular anti‐tumor immune response. We previously reported that loss of HLA class I expression in diffuse large B‐cell lymphoma (DLBCL) of the central nervous system (CNS) and the testis is a common event. Loss of expression and mutations of the light chain of the HLA class I molecule, β 2 ‐microglobulin (β 2 m) have been described in a variety of human tumors and cell lines. In our study, we screened 15 DLBCL cases with a combined loss of HLA class I and β 2 m expression for mutations in the latter gene by direct sequencing. Frame shift mutations in repetitive sequences within the β 2 m gene leading to loss of functional β 2 m were detected in 2 cases. Loss of heterozygosity (LOH) and fluorescent in situ hybridization (FISH) analysis for chromosome 15 exhibited loss of the remaining copy of the β 2 m gene in both cases but also hemizygous deletions and monosomies in 6 additional cases. Since similar mutations in the β 2 m gene have been associated with microsatellite instability (MSI), we used 8 markers to study MSI involvement in DLBCL. Low MSI was more frequent (33%) as compared to nodal DLBCL (n=15) but did not correlate with the β 2 m mutations. Our data indicate that multiple mechanisms lead to downregulation of β 2 m and concomitant loss of HLA class I expression in DLBCL. © 2002 Wiley‐Liss, Inc.