Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites

• DOI: 10.1182/blood.v96.10.3569
• Publication Date: 2019-10-14T07:16:35Z
• Authors: Sietske A. Riemersma; Ekaterina S. Jord...; Roelandt F. J. Schop; Katja Philippo; Leendert H. J. Lo...; Ed Schuuring; Philip M. Kluin
• Keywords: Adult; Lymphoma, B-Cell; Adolescent; Genes, MHC Class II; Loss of Heterozygosity; Central Nervous System Neoplasms; 03 medical and health sciences; 0302 clinical medicine; HLA-DQ Antigens; Humans; In Situ Hybridization, Fluorescence; Aged; HLA-A Antigens; Homozygote; Chromosome Mapping; HLA-DR Antigens; EMC MM-03-24-07; Immunohistochemistry; 3. Good health; Cytogenetic Analysis; Chromosomes, Human, Pair 6; Female; Lymph Nodes; Gene Deletion

AbstractIn B-cell lymphomas, loss of human leukocyte antigen (HLA) class I and II molecules might contribute to immune escape from CD8+ and CD4+ cytotoxic T cells, especially because B cells can present their own idiotype. Loss of HLA expression and the possible underlying genomic alterations were studied in 28 testicular, 11 central nervous system, and 21 nodal diffuse large B-cell lymphomas (DLCLs), the first two sites are considered as immune-privileged sites. The analysis included immunohistochemistry, loss of heterozygosity analysis, and fluorescent in situ hybridization (FISH) on interphase cells and isolated DNA fibers. Total loss of HLA-A expression was found in 60% of the extranodal cases and in 10% of the nodal cases (P < .01), whereas loss of HLA-DR expression was found in 56% and 5%, respectively (P < .01). This was accompanied by extensive loss of heterozygosity within the HLA region in the extranodal DLCLs. In 3 cases, retention of heterozygosity for D6S1666 in the class II region suggested a homozygous deletion. This finding was confirmed by interphase FISH that showed homozygous deletions in the class II genes in 11 of the 18 extranodal lymphomas but in none of the 7 nodal DLCLs (P < .001). Mapping by fiber FISH showed variable deletions that always included HLA-DQ and HLA-DR genes. Hemizygous deletions and mitotic recombinations often involving all HLA genes were found in 13 of 18 extranodal and 2 of 7 nodal lymphomas. In conclusion, a structural loss of HLA class I and II expression might help the B-cell lymphoma cells to escape from immune attack.