A genome-wide association study identifies susceptibility loci for primary central nervous system lymphoma at 6p25.3 and 3p22.1: a LOC Network study

Abstract

BackgroundPrimary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. PCNSL is a distinct subtype of non-Hodgkin lymphoma, with over 95% of tumors belonging to the diffuse large B-cell lymphoma (DLBCL) group. We have conducted a genome-wide association study (GWAS) on immunocompetent patients to address the possibility that common genetic variants influence the risk of developing PCNSL.MethodsWe performed a meta-analysis of 2 new GWASs of PCNSL totaling 475 cases and 1134 controls of European ancestry. To increase genomic resolution, we imputed >10 million single nucleotide polymorphisms using the 1000 Genomes Project combined with UK10K as reference. In addition we performed a transcription factor binding disruption analysis and investigated the patterns of local chromatin by Capture Hi-C data.ResultsWe identified independent risk loci at 3p22.1 (rs41289586, ANO10, P = 2.17 × 10−8) and 6p25.3 near EXOC2 (rs116446171, P = 1.95 x 10−13). In contrast, the lack of an association between rs41289586 and DLBCL suggests distinct germline predisposition to PCNSL and DLBCL. We found looping chromatin interactions between noncoding regions at 6p25.3 (rs11646171) with the IRF4 promoter and at 8q24.21 (rs13254990) with the MYC promoter, both genes with strong relevance to B-cell tumorigenesis.ConclusionTo our knowledge this is the first study providing insight into the genetic predisposition to PCNSL. Our findings represent an important step in defining the contribution of common genetic variation to the risk of developing PCNSL.

Cardiovascular Death Risk in Primary Central Nervous System Lymphoma Patients Treated With Chemotherapy: A Registry-Based Cohort Study

“…Indeed, recent study by Karim Labreche et al. ( 42 ) found that germline variants influenced PCNSL outcomes, and inflammation-related markers (e.g., interleukin-10) are potential targets. The underlying mechanism is still unclear and needs to be investigated further.…”

“…These results suggest that it is necessary to screen appropriate populations (high inflammation risk) for receiving anti-inflammatory treatment besides the differences in anti-inflammatory drugs use. Indeed, recent study by Karim Labreche et al (42) found that germline variants influenced PCNSL outcomes, and inflammation-related markers (e.g., interleukin-10) are potential targets. The underlying mechanism is still unclear and needs to be investigated further.…”

Tracking the Genetic Susceptibility Background of B-Cell Non-Hodgkin’s Lymphomas from Genome-Wide Association Studies

“…Recognized as mature post-germinal B cells (ABC subtype like), the central nervous system (CNS) DLBCL represents only ≤1% of all lymphomas and approximately 2% of all primary CNS tumors; furthermore, 95% of tumors have a comparative histology with systemic DLBCL [ 67 , 75 ]. Since the blood brain barrier impedes R-CHOP treatment, high dose methotrexate (HD-MTX, >3 g/m 2 ) based regimens are the gold standard for PCNSL patients resulting in a five year survival rate of 30% and high risk of clinical neurotoxicity specially in patients > 60 [ 68 , 76 ].…”

“…This study found one variant at loci 6p25.3 (rs116446171; EXOC2; p = 1.95 × 10 −13 ) previously found to be associated with DLBCL risk, other at loci 3p22.1 (rs41289586, ANO10 , p = 2.17 × 10 −8 ) and one strongly associated at HLA allele (rs2395192; between HLA-DRA and HLA-DRB5; p = 1.81 × 10 −7 ). ANO10 is a calcium-activated chloride channel transmembrane protein that might be involved in the innate immune defense and indirect activation of the Ras/Raf/MEK/ERK signaling pathway which affects cell proliferation [ 67 , 69 , 75 , 77 ].…”

Genome-wide association study across pediatric central nervous system tumors implicates shared predisposition and points to 1q25.2 (PAPPA2) and 11p12 (LRRC4C) as novel candidate susceptibility loci

“…The methodology has been employed for a multitude of CNS tumors in adults, but only for a small subset of pediatric brain tumors, and shared susceptibility across tumor types attributable to common variants has not been explored. GWAS on adults have uncovered several low-risk SNPs specific to certain tumor types [14][15][16][17][18]. However, the two published GWAS on brain tumors in children and young adults have only been suggestive of a potential medulloblastoma risk locus at 18p11.23 [19] and of partial overlap in glioma risk loci between different age groups [20].…”