The genetic alterations that define primary central nervous system lymphoma (PCNSL) are incompletely elucidated, and the genomic evolution from diagnosis to relapse is poorly understood. We performed whole-exome sequencing (WES) on 36 PCNSL patients and targeted MYD88 sequencing on a validation cohort of 27 PCNSL patients. We also performed WES and phylogenetic analysis of 3 matched newly diagnosed and relapsed tumor specimens and 1 synchronous intracranial and extracranial relapse. Immunohistochemistry (IHC) for programmed death-1 ligand (PD-L1) was performed on 43 patient specimens. Combined WES and targeted sequencing identified MYD88 mutation in 67% (42 of 63) of patients, CDKN2Abiallelic loss in 44% (16 of 36), and CD79b mutation in 61% (22 of 36). Copy-number analysis demonstrated frequent regions of copy loss (ie, CDKN2A), with few areas of amplification. CD79b mutations were associated with improved progression-free and overall survival. We did not identify amplification at the PD-1/PD-L1 loci. IHC for PD-L1 revealed membranous expression in 30% (13 of 43) of specimens. Phylogenetic analysis of paired primary and relapsed specimens identified MYD88mutation and CDKN2A loss as early clonal events. PCNSL is characterized by frequent mutations within the B-cell receptor and NF-κB pathways. The lack of PD-L1 amplifications, along with membranous PD-L1 expression in 30% of our cohort, suggests that PD-1/PD-L1 inhibitors may be useful in a subset of PCNSL. WES of PCNSL provides insight into the genomic landscape and evolution of this rare lymphoma subtype and potentially informs more rational treatment decisions.
Nayyar N1,2, White MD3,4, Gill CM1, Lastrapes M1,2,5, Bertalan M1, Kaplan A1, D’Andrea MR1, Bihun I1, Kaneb A1, Dietrich J1,3,4, Ferry JA6, Martinez-Lage M3,6, Giobbie-Hurder A5, Borger DR1,3, Rodriguez FJ7, Frosch MP3,6, Batchelor E1, Hoang K1, Kuter B1, Fortin S1, Holdhoff M7, Cahill DP1,3,4,8, Carter S2,5,9, Brastianos PK1,2,3,4, Batchelor TT1,3,4.
Blood Adv. 2019 Feb 12;3(3):375-383. doi: 10.1182/bloodadvances.2018027672.