MiR-SNPs as markers of toxicity and clinical outcome in Hodgkin lymphoma patients

Abstract

Background: In recent years, microRNA (miRNA) pathways have emerged as a crucial system for the regulation of tumorogenesis. miR-SNPs are a novel class of single nucleotide polymorphisms that can affect miRNA pathways.

Design and methods: We analyzed eight miR-SNPs by allelic discrimination in 141 patients with Hodgkin lymphoma and correlated the results with treatment-related toxicity, response, disease-free survival (DFS) and overall survival (OS).

Results: The KRT81 (rs3660) GG genotype was associated with an increased risk of neurological toxicity (P = 0.016), while patients with XPO5 (rs11077) AA or CC genotypes had a higher rate of bleomycin-associated pulmonary toxicity (P = 0.048). Both miR-SNPs emerged as independent factors in the multivariate analysis. The XPO5 AA and CC genotypes were also associated with a lower response rate (P = 0.036). XPO5 (P = 0.039) and TRBP (rs784567) (P = 0.022) genotypes emerged as prognostic markers for DFS, and XPO5 was also associated with OS (P = 0.033). In the multivariate analysis, only XPO5 emerged as an independent prognostic factor for DFS (HR: 2.622; 95%CI 1.039-6.620; P = 0.041). Given the influence of XPO5 and TRBP as individual markers, we then investigated the combined effect of these miR-SNPs. Patients with both the XPO5 AA/CC and TRBP TT/TC genotypes had the shortest DFS (P = 0.008) and OS (P = 0.008).

Conclusion: miR-SNPs can add useful prognostic information on treatment-related toxicity and clinical outcome in Hodgkin lymphoma and can be used to identify patients likely to be chemoresistant or to relapse.

Figure 1. Clinical outcomes according to miR-SNPs.

DFS according to TRBP, XPO5 and MIR196A2, and OS according to XPO5. (A) Mean DFS for 37 patients (31.6%) with the TRBP CC genotype was 124 months (95% CI, 112–136) vs. 86.8 months (95% CI, 74–89) for those with the TT or TC genotype (P = 0.022). (B) Mean DFS for 62 patients (56.3%) with the XPO5 AC genotype was 114.2 months (95% CI, 101–127) vs. 85.8 months (95% CI, 68–104) for patients with the AA or CC genotype (P = 0.039). (C) A trend towards an association between the MIR196A2 genotype and DFS was also observed; mean DFS was 115 months (95% CI, 99–131) for patients with the CC genotype, compared to 81 months (95% CI, 66–97) for those with the CT or TT genotype (P = 0.07). (D) Mean OS for 71 patients (54.2%) with the XPO5 AC genotype was 135.3 months (95% CI, 127–143) vs. 114.2 months (95% CI, 99–129) for those with the AA or CC genotype (P = 0.033).

Figure 2

Clinical outcomes in early and advanced HL according to miR-SNPs. DFS in early-stage HL patients according to KRT81 and TRBP and in advanced HL patients according to XPO5. And OS in advanced-stage HL patients according to XPO5. (A) DFS was 72.3 months (95% CI, 59–86) for patients with the KRT81 CG genotype and 114.3 months (95% CI, 103–125) for those with the TT or TC genotype (P = 0.037). (B) A trend towards an association between the TRBP genotype and DFS in early-stage patients was also observed; mean DFS was 117 months (95% CI, 105–129) for patients with the TT genotype, compared to 92 months (95% CI, 78–106) for those with the CC or TC genotype (P = 0.081). (C) All patients with the XPO5 AC genotype were disease-free at the time of this analysis, while mean DFS among patients with the AA or CC genotype was 30.9 months (95% CI, 18–44) (P = 0.002). (D) OS was 133 months (95% CI, 118–148) in patients harboring the AC genotype compared to 74 months (95% CI, 55–94) for those with the AA or CC genotype (P = 0.035).

Figure 3

DFS and OS according to the combination of TRBP and XPO5 genotypes. Patients with both the XPO5 AA/CC and TRBP TT/TC genotypes had the worst prognosis. (A) DFS was 74 months (95% CI, 54–94) for patients with the unfavorable combination, compared to 114 months (95% CI, 102–126) for those with other combinations (P = 0.008). (B) OS was 103 months (95% CI, 86–120) for patients with the unfavorable combination and 135 months (95% CI, 128–143) for those with other combinations (P = 0.008).