Abstract
<div>Abstract<p><b>Purpose:</b> Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance.</p><p><b>Experimental Design:</b> We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (<i>n</i> = 29) and whole-exome sequencing (<i>n</i> = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis.</p><p><b>Results:</b> All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (<i>HLA</i> locus), (ii) 6q loss, (iii) <i>CDKN2A</i> homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of <i>PRMD1</i>, <i>TOX</i>, and <i>DOCK5</i> and the amplification of <i>HDAC9</i> were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in <i>MYD88</i> and <i>TBL1XR1</i> in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (<i>P</i> = 0.006 and <i>P</i> = 0.01) and <i>CDKN2A</i> homozygous deletion (<i>P</i> = 0.02 and <i>P</i> = 0.01) were significantly associated with shorter progression-free survival and overall survival.</p><p><b>Conclusions:</b> Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially <i>MYD88</i> and <i>TBL1XR1</i> mutations activating the NF-κB signaling pathway, which may be promising targets for future therapeutic strategies. <i>Clin Cancer Res; 18(19); 5203–11. ©2012 AACR</i>.</p></div>
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