A Comprehensive High-Resolution Genomic Analysis of Primary Central Nervous System Lymphomas Shows a Highly Complex Karyotype Characterized by Abnormalities Affecting Multiple Genes Involved in Critical Pathways Associated with Lymphocyte Maturation and Survival.
Authors: Braggio Esteban , Law Mark , Macon W.R , O'Neill Brian Patrick , Fonseca Rafael 
Published: October 2019

Abstract 4637

Primary central nervous system lymphoma (PCNSL) is an aggressive form of extra-nodal, high-grade, non-Hodgkin B-cell neoplasm. It originates in the brain, leptomeninges, spinal cord or eyes and typically remains confined to the CNS. Further immunophenotypic characterization has revealed that these tumors have overlapping features of germinal center and activated B-cell differentiation. Although the cells of origin are lymphocytes, PCNSL should be considered a brain tumor because its therapeutic challenges resemble those of other brain tumors. Regarding the molecular pathogenesis of PCNSL, there is significantly less information in comparison with systemic lymphomas. The aim of this study was to perform a comprehensive high-resolution genomic analysis in a cohort of PCNSL cases to better characterize the disease at chromosomal and gene level. Copy-number abnormalities were analyzed in seven PCNSL by array-based comparative genomic hybridization (aCGH) using SurePrint G3 (1 million probes, ∼4 Kb resolution) microarray (Agilent). Overall, PCNSL cases were characterized by highly complex genomes with a median of 23 copy-number abnormalities per patient (range 16-49). The whole genomic regions affected in abnormalities correspond to areas between 3% and 29% of the human genome. Globally, 43 chromosomal regions were affected in a recurrent fashion (24 areas involved in recurrent deletions and 19 in copy-number gains). Gain of 12q12-q24.33 and losses of 9p21.3 and 6q were the most common abnormalities found in 71% patients each (5 out of 7). There was not a unique deleted region on 6q to all patients, with 6q14.1-q14.3, 6q16.3-q22.2 and 6q25.3-q26 losses being found in 4 out of 5 cases with 6q deletions. None of these regions include PTPRK, which has been previously proposed as a potential modulator of PCNSL progression. CDKN2A was the sole gene included in all cases with 9p21.3, being biallelically deleted in two out of 5 cases. Minimal deleted genes were also delineated in 3p21.1 (minimal affected area of 0.03Mb) and 3q26.32 (0.27Mb) in 44% of cases each. Those regions included PRKCD (inhibits B-cell growth through transcriptional regulation of IL-6) and TBL1XR1 (corepressor of nuclear hormone receptor), respectively. Overall, a total of 22 genes were included in homozygous deletions in at least one case. Besides CDKN2A (cell cycle), other genes of interest associated with the development and activation of T cells (TOX, CD58) were biallelically affected. Focal monoallelic deletions affecting negative regulators of the NFkB signaling pathway (MAP4K1, TANK, TAX1BP1, TRIB3), cell cycle (RB1) and immune-cell regulation (SIRPB1, CBLB, NFATC2) were also identified. Of interest, no copy-number abnormalities were identified affecting TP53 in any patient. Several chromosomal breakpoints were identified inside genes that encodes transcription factors previously identified as being part of fusion protein in other hematological malignancies (FOXP1, ETV6 and NCOA2) thus suggesting the potential existence of fusion proteins including these genes. Cytogenetic and genetic approaches are being currently used to validate this hypothesis. This is the first study characterizing a cohort of PCNSL cases by using this comprehensive high-resolution approach. Regarding the small number of cases analyzed so far, we can confirm the existence of a highly complex genome, mainly characterized by abnormalities affecting a plethora of genes involved in lymphocyte development, activation and NF-kB signaling pathways regulation. Molecular analyses are ongoing to validate these findings in a larger cohort of PCNSL patients.

Disclosures:

Fonseca: Otsuka: Consultancy; BMS: Consultancy; Amgen: Consultancy; Medtronic : Consultancy; Genzyme: Consultancy.