Amplification of 9p24.1 in diffuse large B-cell lymphoma identifies a unique subset of cases that resemble primary mediastinal large B-cell lymphoma

Yucai Wang,Keenan Hartert,Kerstin Wenzl,Rong He,Thomas M Habermann,Grzegorz S Nowakowski,Andrew L Feldman,Jordan E Krull,Patricia T Greipp,Matthew J Maurer,Yan W Asmann,Thomas E Witzig,Stephen M Ansell,Susan L Slager,Brian K Link,Michelle K Manske,Anne J Novak,James R Cerhan,Vivekananda Sarangi

doi:10.1038/s41408-019-0233-5

Yucai Wang, Keenan Hartert + Show 17 more

Open Access

https://doi.org/10.1038/s41408-019-0233-5

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Abstract

Copy number alterations (CNAs) of 9p24.1 occur frequently in Hodgkin lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), primary central nervous system lymphoma, and primary testicular lymphoma, resulting in overexpression of PD-L1 and sensitivity to PD-1 blockade-based immunotherapy. While 9p24.1 CNA was also reported in diffuse large B-cell lymphoma (DLBCL), little is known about its molecular or clinical significance. In this study, we analyzed the prevalence of 9p24.1 CNA in newly diagnosed DLBCL and examined its association with PD-L1, PD-L2, and JAK2 expression, clinical characteristics, and outcome. We found that 10% of DLBCL cases had CNA of 9p24.1, with 6.5% gains, and 3.5% amplifications. Only the cases with a 9p24.1 amplification had high levels of PD-L1, PD-L2, and JAK2 expression. Gains or amplifications of 9p24.1 were associated with a younger age and the ABC/non-GCB subtype. Compared with DLBCL cases without 9p24.1 CNA, the cases with a 9p24.1 amplification had a trend of better event-free survival. Furthermore, the amplification cases had a gene expression and mutation profile similar to those of PMBCL. Our data suggest that amplification of 9p24.1 identifies a unique subset of DLBCL with clinical and molecular features resembling PMBCL that may be amenable to PD-1 blockade-based immunotherapy.

Highlights

Introduction Diffuse largeB-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL)
We find that the 9p24.1 amplification cases have clinical and molecular features that resemble primary mediastinal large B-cell lymphoma (PMBCL) and represent a unique subset of diffuse large B-cell lymphoma (DLBCL) that might be amenable to immune checkpoint blockade therapy
Using available RNASeq data on 31 of the cases used for Copy number alterations (CNAs) analysis (3 amplifications, 2 gains, and 26 no gains), we examined the expression of CD274/Programmed death-ligand 1 (PD-L1), PDCD1LG2/ PD-L2, and JAK2

Summary

Introduction

Introduction Diffuse largeB-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). Copy number alterations (CNA) of 9p24.1, including chromosomal amplification, gain, polysomy, or translocation, are one of the hallmarks of classical Hodgkin lymphoma (cHL)[17,18], and frequently occur in extranodal large B-cell lymphomas, such as primary mediastinal large B-cell lymphoma (PMBCL)[17,19,20,21,22], primary central nervous system lymphoma (PCNSL)[22], and primary testicular lymphoma (PTL)[22] These genomic alterations can lead to increased expression of key genes in the region, including PDCD1LG2/PD-L2, CD274/PDL1, and JAK217,18. Immune checkpoint inhibitors targeting PD-1 such as nivolumab or pembrolizumab have proven to be efficacious in treating relapsed and/or refractory cHL25–28, and have been shown to be effective in PMBCL, PCNSL, and PTL29,30

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