Analysis of microsatellite instability in primary mediastinal large B-cell lymphoma: Focus on PD-L1/PD-L2 and CIITA
Authors: Abdurashidova R. R. , Risinskaya N. V. , Mangasarova Y. K. , Surin V.L. V. L. , Shupletsova I. A. , Chabaeva Yu. A. , Magomedova A. U. , Abramova T. V. , Nikulina E. E. , Iusupov R. I. , Kulikov S. M. , Zvonkov E. E. , Kovrigina A. M. , Sudarikov A. B. 
Published: November 2024

Introduction. Primary mediastinal large B-cell lymphoma (PMBCL) is a rare non-Hodgkin lymphoma. Considering the immunophenotype of PMBCL, which differs from diffuse large B-cell lymphoma (DLBCL), Microsatellite Repeat (MSR) aberrations in regions flanking PD-L1/PD-L2 and CIITA genes were investigated.

Aim: to study the prevalence of MSR aberrations in 19 loci of the COrDIS Plus panel and in the regions of the PD-L1/PD-L2, CIITA genes in PMBCL and DLBCL, and to compare it with the expression level of PD-L1 and HLA-DR in PMBCL.

Materials and methods. The study included 137 patients, 86 (62,8%) with PMBCL and 51 (37.2%) with DLBCL. The analysis was conducted using the standard COrDIS Plus panel, which includes a set of primers for 19 loci of tetranucleotide repeats. The allelic imbalance (AI) of MSR close to the PD-L1/PD-L2 genes (9p24.1) (n = 68/86 (79.1%) for PMBCL, n = 36/51 (70.6 %) for DLBCL) and CIITA (16p13.13) (n = 71/86 (82.6 %) for PMBCL, n = 29/51 (56.9 %) for DLBCL) was investigated using STR analysis. Patients with homozygous inheritance for each of the studied markers were excluded from further analysis due to the inability to assess loss of heterozygosity (LOH). The expression of PD-L1 and HLA-DR was assessed by immunohistochemistry in 27/86 (31.4 %) PMBCL patients.

Results. Homozygosity for both markers near the PD-L1/PD-L2 genes was found in 5/68 (7.4 %) of PMBCL patients and 10/36 (27.8 %) of DLBCL patients (p = 0.008). Aberrations of MSR flanking the PD-L1/PD-L2 genes were detected in 33/63 (52.4%) of PMBCL patients and 5/26 (19.2 %) of DLBCL patients (p = 0.003; OR 5.8; 95% CI [2.8–18.7]). Homozygosity for both markers near the CIITA gene was identified in 8/71 (11.3%) of PMBCL patients and 7/29 (24.1%) of DLBCL patients (p = 0.13). AI near the CIITA gene was found in 24/63 (38.1 %) of PMBCL patients, while no changes in the CIITA region were observed in the DLBCL group (p = 0.0001; OR 14.3; 95% CI [2.8–262.5]). Using the COrDIS Plus panel, the frequencies of tetranucleotide repeat aberrations did not significantly differ between PMBCL and DLBCL (p = 0.78 for LOH, p = 0.17 for EMAST). No correlation was found between MSR aberrations near the PD-L1/PD-L2 and CIITA genes and the expression levels of PD-L1 and HLA-DR (p = 0.402 and 0.668, respectively).

Conclusion. A statistically significant more frequent alteration in the MSR marker profile of the PD-L1/PD-L2 and CIITA gene regions was found in PMBCL patients compared to DLBCL. Chromosomal microarray analysis in 2 out of 3 PMBCL cases revealed genetic aberrations involving the PD-L1/PD-L2 and/or CIITA genes, and AI of these genes was observed simultaneously with the MSR profile evaluation. This confirms the different pathogenesis of these diseases and suggests that the presence of AI in these loci indicates the involvement of these genes in the pathogenesis. There is no correlation between AI in the PD-L1/PD-L2 and CIITA gene regions and the expression of PD-L1 and HLA-DR, respectively.