Work

Host Genetic Variation in the Tnf and Nf‐ĸb Pathways and Prognosis in Mantle Cell Lymphoma: an Analysis of 2 Studies

Year: 2017

Type: article

Abstract: Introduction: Mantle cell lymphoma (MCL) is a generally incurable non-Hodgkin lymphoma characterized by the t(11;14) translocation that leads to overexpression of cyclin D1. Multiple genes involved in the tumor necrosis factor (TNF) and nuclear factor-κB (NF-κB) pathways have been reported to be up-regulated in MCL. NF-κB has been shown to be constitutively active in MCL and may play a key role in the growth and survival of MCL cells. We investigated whether host germline variation in the TNF and NF-ĸB pathway genes is associated with overall survival (OS) in MCL. Methods: In a discovery dataset from the NCI-SEER Survival Study, we evaluated the association of 41 candidate genes and 486 tag single nucleotide polymorphisms (SNPs) with OS in 39 MCL patients using a gene-level test. We then attempted to replicate individual SNPs from the top candidate genes (P ≤ .15) in an independent dataset of 101 MCL patients from the molecular epidemiology resource (MER) of the University of Iowa and Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). We used Cox proportional hazards regression to evaluate the association of genes (defined by principal components) and SNPs with OS after adjusting for clinical factors and treatment. For SNP associations, we estimated hazard ratios (HRs) and 95% confidence intervals (CI) from Cox regression models. Results: In the NCI-SEER discovery cohort, 8 genes (NFKBIL1, TNFSF13B, TNFRSF25, TRAF5, NFKB1, RELB, IRF4, NFKBIA) were potentially associated with OS (P ≤ .15). Association of OS was replicated for 3 of these genes at the SNP level in the MER cohort: TNFRSF25 (rs3138156), TRAF5 (rs3738199, rs6684874, rs12569232), and RELB (rs10424046, rs1560725). We then combined the SNP level data in a meta-analysis of the 2 cohorts. The TNFRSF25 SNP rs3138156 was associated with inferior survival (P = .0047): compared to patients with the AA genotype, those with the AG (HR = 3.04; 95% CI, 1.41-6.56) had inferior OS (no GG genotype was seen in the cohorts). The TRAF5 SNP rs3738199 was also associated with inferior survival (P = .00086): compared to patients with the AA genotype, those with the AG (HR = 1.81; 95% CI, 0.99-3.32) and GG (HR = 4.11; 95% CI, 1.86-9.04) genotypes had inferior OS. Finally, the RELB SNP rs10424046 was associated with superior survival (P = .0062): compared to the patients with GG genotype, those with the CG (HR = 0.45; 95% CI, 0.25-0.82) and CC (HR = 0.36; 95% CI, 0.17-0.78) genotypes had better OS. Conclusions: Germline variation in the TNF and NF-κB pathway genes TNFRSF25, TRAF5, and RELB were associated with OS in MCL after adjustment for clinical and treatment factors. The genetic variation in the TNF and NF-κB pathway genes may play a role in disease progression and overall survival in MCL. The role of the TNF and NF-κB pathways in the pathogenesis of MCL, and targeting these pathways for therapy in MCL, should be further explored. Keywords: mantle cell lymphoma (MCL); NF-kB; SNP

Source: Hematological Oncology

DOI: 10.1002/hon.2438_4