Menashe, Idan

Abstract Background. Non-Hodgkin lymphoma (NHL) case-control studies consistently demonstrate the G-308A promoter polymorphism in the tumor necrosis factor gene on chromosome 6p21.3 to be associated with increased risk of the NHL subtype, diffuse large B-cell lymphoma (DLBCL). Initial results from a genome-wide association study have implicated a polymorphism located on 6p21.33 with increased risk of the follicular lymphoma subtype. In the present analysis, we evaluated 488 candidate gene regions (defined as 20kb 5’, 10kb 3’) and their relation to risk for NHL and the DLBCL and follicular lymphoma subtypes with a particular focus on genes within the 6p21 chromosomal region. Methods. We genotyped 6679 tag single nucleotide polymorphisms (SNPs) in 947 cases and 826 population-based controls from a multicenter U.S.-based case-control study. Genotyping was conducted on a custom-designed Illumina Infinium assay at the NCI Core Genotyping Facility. We obtained a gene region-level summary of association by computing the minimum p-value (“minP test”). We used logistic regression to evaluate the association between single nucleotide polymorphism (SNP) genotypes and haplotypes with NHL (adjusted for sex, race and age). For NHL subtypes, we conducted polytomous multivariate unconditional logistic regression. We evaluated tests for trend under the co-dominant model used a three-level ordinal variable for each SNP. Results. We identified 34 gene regions significantly associated with all NHL (p <0.05). The three most significant gene regions were all found on chromosome 6p21.3 (RING1/RXRB; AIF1/BAT2; BAT4, p=0.001). Within those gene regions, the most significant SNPs (p<0.0002) were rs2855429 and rs213213 (RING1/RXRB), rs2857597 and rs3130071 (AIF1/BAT2), and rs3115667 (BAT4). All five SNPs were statistically significantly associated with both DLBCL and follicular lymphoma. Additional gene regions on 6p21.3 associated with NHL include MSH5 (p=0.009), FAM46A (p=0.01) and TNXB/CREBL1 (p=0.04). Stratification by age and gender did not alter our results; consistent results were observed in analyses restricted to non-Hispanic Caucasians. Haplotype analyses yielded the same regions and SNPs of significance. Detailed analysis of the 6p21.3 region will be presented. Conclusions. Our results further implicate gene variants within the 6p21.3 chromosomal region in NHL etiology. Full characterization of the 6p21.3 region and identification of functional variants within this region are warranted for understanding lymphomagenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 935.

Abstract Background: There is growing evidence linking genetic variations to non–Hodgkin lymphoma (NHL) etiology. To complement ongoing agnostic approaches for identifying susceptibility genes, we evaluated 488 candidate gene regions and their relation to risk for NHL and NHL subtypes. Methods: We genotyped 6,679 tag single nucleotide polymorphisms (SNPs) in 947 cases and 826 population-based controls from a multicenter U.S. case–control study. Gene-level summary of associations were obtained by computing the minimum P value (“minP test”) on the basis of 10,000 permutations. We used logistic regression to evaluate the association between genotypes and haplotypes with NHL. For NHL subtypes, we conducted polytomous multivariate unconditional logistic regression (adjusted for sex, race, age). We calculated P-trends under the codominant model for each SNP. Results: Fourteen gene regions were associated with NHL (P < 0.01). The most significant SNP associated with NHL maps to the SYK gene (rs2991216, P-trend = 0.00005). The three most significant gene regions were on chromosome 6p21.3 (RING1/RXRB; AIF1; BAT4). Accordingly, SNPs in RING1/RXRB (rs2855429), AIF1 (rs2857597), and BAT4 (rs3115667) were associated with NHL (P-trends ≤ 0.0002) and both diffuse large B-cell and follicular lymphomas (P-trends < 0.05). Conclusions: Our results suggest potential importance for SYK on chromosome 9 with NHL etiology. Our results further implicate 6p21.3 gene variants, supporting the need for full characterization of this chromosomal region in relation to lymphomagenesis. Impact: Gene variants on chromosome 9 may represent a new region of interesting for NHL etiology. The independence of the reported variants in 6p21.3 from implicated variants (TNF/HLA) supports the need to confirm causal variants in this region Cancer Epidemiol Biomarkers Prev; 20(1); 42–9. ©2011 AACR.

Abstract Caspases play a critical role in regulation of apoptosis, cell differentiation, inflammation, and innate immunity, and several are mutated or have altered expression in non-Hodgkin lymphoma (NHL). To study the impact of genetic variation in caspases on NHL risk, we analyzed tag single nucleotide polymorphisms (SNPs) in 12 caspase and related genes in 3 population-based case-control studies (1946 cases and 1808 controls). Gene-based analysis, adjusting for the number of tagSNPs genotyped in each gene, showed significant associations for CASP8, CASP9, and CASP1. SNP-based analysis showed that CASP8 rs6736233 (odds ratio (OR) CG = 1.21; ORCC = 2.13; P trend = .011); CASP9 rs4661636 (ORCT = 0.89; ORTT = 0.77; P trend = .011); and CASP1 rs1785882 (ORAT = 1.12; ORAA = 1.30; P trend = .0054) were significantly associated with NHL risk and consistent across studies. It is noteworthy that genetic variants in CASP8 were associated with risk of all major NHL subtypes. Our findings suggest that genetic variation in caspases may play an important role in lymphomagenesis.

AbstractChromosomal translocations are the hallmark genetic aberration in non–Hodgkin lymphoma (NHL), with specific translocations often selectively associated with specific NHL subtypes. Because many NHL-associated translocations involve cell cycle, apoptosis, and lymphocyte development regulatory genes, we evaluated NHL risk associated with common genetic variation in 20 candidate genes in these pathways. Genotyping of 203 tag single nucleotide polymorphisms (SNP) was conducted in 1,946 NHL cases and 1,808 controls pooled from 3 independent population-based case-control studies. We used logistic regression to compute odds ratios (OR) and 95% confidence intervals (CI) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. We observed the most striking associations for tag SNPs in the proapoptotic gene BCL2L11 (BIM) and BCL7A, which is involved in a rare NHL-associated translocation. Variants in BCL2L11 were strongly related to follicular lymphoma only, particularly rs3789068 (ORAG, 1.41; 95% CI, 1.10-1.81; ORGG, 1.65; 95% CI, 1.25-2.19; Ptrend = 0.0004). Variants in BCL7A were strongly related to diffuse large B-cell lymphoma only, particularly rs1880030 (ORAG, 1.34; 95% CI, 1.08-1.68; ORAA, 1.60; 95% CI, 1.22-2.08; Ptrend = 0.0004). The associations for both variants were similar in all three studies and supported by haplotype analyses. We also observed notable associations for variants in BCL6, CCND1, and MYC. Our results support the role of common genetic variation in cell cycle, apoptosis, and lymphocyte development regulatory genes in lymphomagenesis, and suggest that effects may vary by NHL subtype. Replication of our findings and further study to identify functional SNPs are warranted. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1259–70)