Genome-Wide Analysis Uncovers Novel Recurrent Alterations in Primary Central Nervous System Lymphomas

Abstract

Purpose: Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the central nervous system. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain.

Experimental design: We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing.

Results: Biallelic inactivation of TOX and PRKCD was recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. In addition, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11, and translocations IgH-BCL6. Overall, B-cell receptor/Toll-like receptor/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation.

Conclusions: In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas.

Figure 1

Overview of copy number abnormalities identified in the cohort of PCNSL analyzed. Chromosomes 1 to Y are represented from left to right. Dark gray blocks represent chromosome gains, whereas light gray blocks represent chromosome losses. The amplitude in each abnormal region represents the incidence of each copy- number abnormality in the studied cohort. Genes found in recurrent minimal aberrant regions (>25%) are indicated.

Figure 2

Recurrent mutations in PCNSL. The columns of the heatmap represent individual patients. Type of mutation found is color-coded. In cases with multiple mutations in the same gene, a combination of colors (more than one type of mutations) or numbers indicating the number of mutations found (more than one mutation of the same type) was used. Right: Histogram showing the incidence of mutations found in each gene.

Figure 3

Integration of copy-number and sequencing data shows a set of recurrent abnormalities. List of genes that were affected with activating mutations/translocations/high copy gain (top) or biallelic loss (bottom).

Figure 4

Protein Kinase C delta (PRKCD) is recurrently inactivated in PCNSL. Concomitant PRKCD monoallelic deletions (top figure) and mutations affecting both alleles (bottom figures) were recurrently found in PCNSL.

Figure 5

Homozygous (top 2 samples) and focal heterozygous deletions (bottom 3 samples) affecting TOX were recurrently found in PCNSL.