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

Background: Primary 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.

Methods: We 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.

Results: We 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.

Conclusion: To 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.

Keywords: GWAS; cancer susceptibility; primary CNS lymphoma.

Fig. 1

Manhattan plot of association P-values. Shown are the genome-wide −log₁₀P-values (two-sided) of >10 million successfully imputed autosomal SNPs in 475 cases and 1134 controls. The red horizontal line represents the genome-wide significance threshold of P = 5.0 × 10⁻⁸.

Fig. 2

Regional plots of association results and recombination rates for new risk loci for primary cerebral nervous system lymphoma. Results shown for (A) 6p25 and (B) 3q21. Plots (drawn using visPig../../../../../../data_oupjournals/production/neuonc/noz088/from_client/accepted_manuscripts/Scales, - _ENREF_58) show association results of both genotyped (triangles) and imputed (circles) SNPs in the GWAS samples and recombination rates. −log₁₀P values (y-axis) of the SNPs are shown according to their chromosomal positions (x-axis). The sentinel SNP in each combined analysis is shown as a large circle or triangle and is labeled by its rsID. The color intensity of each symbol reflects the extent of linkage disequilibrium with the top genotyped SNP, white (r² = 0) through to dark red (r² = 1.0). Genetic recombination rates, estimated using 1000 Genomes Project samples, are shown with a light blue line. Physical positions are based on National Center for Biotechnology Information build 37 of the human genome. Also shown are the chromatin-state segmentation track (ChromHMM) for lymphoblastoid cells using data from the HapMap ENCODE Project, and the positions of genes and transcripts mapping to the region of association. The top track represents Capture Hi-C promoter contacts in GM12878 cells. The color intensity of each contact reflects the interaction score.

Fig. 2

Regional plots of association results and recombination rates for new risk loci for primary cerebral nervous system lymphoma. Results shown for (A) 6p25 and (B) 3q21. Plots (drawn using visPig../../../../../../data_oupjournals/production/neuonc/noz088/from_client/accepted_manuscripts/Scales, - _ENREF_58) show association results of both genotyped (triangles) and imputed (circles) SNPs in the GWAS samples and recombination rates. −log₁₀P values (y-axis) of the SNPs are shown according to their chromosomal positions (x-axis). The sentinel SNP in each combined analysis is shown as a large circle or triangle and is labeled by its rsID. The color intensity of each symbol reflects the extent of linkage disequilibrium with the top genotyped SNP, white (r² = 0) through to dark red (r² = 1.0). Genetic recombination rates, estimated using 1000 Genomes Project samples, are shown with a light blue line. Physical positions are based on National Center for Biotechnology Information build 37 of the human genome. Also shown are the chromatin-state segmentation track (ChromHMM) for lymphoblastoid cells using data from the HapMap ENCODE Project, and the positions of genes and transcripts mapping to the region of association. The top track represents Capture Hi-C promoter contacts in GM12878 cells. The color intensity of each contact reflects the interaction score.