Recurrent genetic alterations in primary central nervous system lymphoma of immunocompetent patients.

Abstract

2023 Background: Little is known about the molecular pathogenesis of primary central nervous system lymphoma (PCNSL) in immunocompetent patients. Our objective was to identify the genetic changes involved in PCNSL oncogenesis and evaluate their clinical relevance. Methods: Twenty nine and four newly diagnosed, HIV-negative PCNSL patients were investigated using high-resolution single nucleotide polymorphism (SNPa) arrays (Infinium Illumina Human 610-Quad SNP array-Illumina; validated by real-time quantitative polymerase chain reaction) and whole-exome sequencing respectively. Molecular results were correlated with prognosis. Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received high-dose methotrexate-based polychemotherapy without radiotherapy as an initial treatment.SNPa analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic changes were (i) 6p21.32 loss (79%), corresponding to the HLA locus; (ii) 6q loss (27-37%); (iii) CDKN2A homozygous deletions (45%); (iv) 12q12-q22 (27%); (v) chromosome 7q21 and 7q31 gains (20%). Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 (L265P hot spot mutation) and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (p=0.006 and p=0.01), and CDKN2A homozygous deletion (p=0.02 and p=0.01) were significantly associated with shorter progression free survival and overall survival. Conclusions: Our study identified novel genetic alterations in PCNSL, such as MYD88 and TBL1XR1 somatic mutations, which would both contribute to the constitutive activation of the NFkB signaling pathway and represent potential promising targets for future therapeutic strategies.