MYD88 L265P mutation and CDKN2A loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas

Abstract

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, CDKN2A biallelic 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 MYD88 mutation 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.

Graphical abstract

Figure 1.

Somatic mutations in PCNSL. Somatic mutations and copy-number aberrations in PCNSL. The plot includes primary (-P) and relapse samples (-R). The significance of mutations in each gene is shown to the right by a false discovery rate (FDR) q value.

Figure 2.

Significant CNAs in the cohort. Chromosomal regions of copy loss indicated in blue. Areas of copy gain indicated in red.

Figure 3.

Phylogenetic trees. Phylogenetic trees from 4 different patients with relapsed PCNSL. (A-C) Comparison of the primary tumor with the relapsed specimen: primary and brain relapse (A), primary and systemic relapse (B), and primary and testicular relapse (C). (D) Comparison between simultaneous occurrence of brain and skin lymphoma. The width of each line corresponds to the CCF. Subpopulations (CCF <1) are labeled at the end of each line. The length of the line corresponds to the number of mutations that are present. Relevant mutations are indicated on each branch. Gray, shared; blue, private to primary tumor specimen in the CNS; purple, private to the relapsed or extracranial tumor specimen.