Prognostic significance of host immune gene polymorphisms in follicular lymphoma survival

Abstract

Recent gene-expression data have suggested that host immune genetic signatures may predict outcomes in patients with follicular lymphoma. We evaluated the hypothesis that germ line common variation in candidate immune genes is associated with survival. Cox models were used to estimate hazard ratios (HR) and corresponding 95% confidence intervals for individual SNPs after accounting for age, clinical, and other demographic factors. The median age at diagnosis of the 278 patients was 57 years, and 59 (21%) of the patients died during follow-up, with a median follow-up of 59 months (range, 27-78 months) for surviving patients. SNPs in IL8 (rs4073; HR(TT)=2.14, 1.26-3.63), IL2 (rs2069762; HR(GT/TT) = 1.80, 1.06-3.05), IL12B (rs3212227; HR(AC/CC)=1.83, 1.06-3.06), and IL1RN (rs454078; HR(AA)=1.93, 1.11-3.34) were the most robust predictors of survival. A summary score of the number of deleterious genotypes from these genes was strongly associated with survival (P=.001). A risk score that combined the 4 SNPs with the clinical and demographic factors was even more strongly associated with survival (P<.001); the 5-year Kaplan-Meier survival estimates were 96% (93%-100%), 72% (62%-83%), and 58% (48%-72%) for groups at low, intermediate, and high risk, respectively. Common variation in host immune genes warrants further evaluation as a promising class of prognostic factors in follicular lymphoma.

Figure 1

Data analysis schematic.

Figure 2

Summary of Phase 3 results. Panel A shows the reduction in the -2 log likelihood when comparing the best 1 SNP, 2 SNP,…9 SNP model from the study data (solid line) as well as expected reduction due to chance (dashed line). Panel B ranks the percentage of 1000 stepwise bootstrap Cox models in which a SNP was included. The top 4 SNPs in the bootstrap model are the same 4 SNPs in the best 4-SNP risk model.

Figure 3

Results for the 4 SNP risk score. Kaplan-Meier curves by the number of deleterious genotypes from the 4 SNP Risk Score based on IL8 (rs4073), IL2 (rs2069762), IL12B (rs3212227), and IL1RN (rs454078).

Figure 4

Results for the summary SNP and clinical and demographic risk score. Kaplan-Meier curves by level of the combined SNP and clinical and demographic risk score.

Figure 5

Time-dependent ROC analysis. Figure shows the time-dependent receiver-operator (ROC) analysis for the clinical and demographic risk score, the 4 SNP risk score, the combined SNP and clinical and demographic risk score, and the IPI from a previously published study by Dave et al.