CHN1 is a Novel Prognostic Marker for Diffuse Large B-Cell Lymphoma

Abstract

Purpose: Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy. Thirty to forty percent of DLBCL patients still experience relapse or develop refractory disease even with standard immunochemotherapy, leading to a poor prognosis. Currently, although several gene-based classification methods can be used to predict the prognosis of DLBCL, some patients are still unable to be classified. This study was performed to identify a novel prognostic biomarker for DLBCL.

Patients and methods: A total of 1850 B-cell non-Hodgkin lymphoma (B-NHL) patients in 8 independent datasets with microarray gene expression profiles were retrieved from the Gene Expression Omnibus (GEO) database and Lymphoma/Leukemia Molecular Profiling Project (LLMPP). The candidate genes were selected through three filters in a strict pipeline. Survival analysis was performed in two independent datasets of patients with both gene expression data and clinical information. Gene set enrichment analysis (GSEA) and the CIBERSORT algorithm were used to explore the biological functions of the genes.

Results: We identified 6 candidate genes associated with the clinical outcome of DLBCL patients: CHN1, CD3D, CLU, ICOS, KLRB1 and LAT. Unlike the other five genes, CHN1 has not been previously reported to be implicated in lymphoma. We also observed that CHN1 had prognostic significance in important clinical subgroups; in particular, high CHN1 expression was significantly related to good outcomes in DLBCL patients with the germinal center B-cell-like (GCB) subtype, stage III-IV, or an International Prognostic Index (IPI) score > 2. Multivariate Cox regression analysis of the two datasets showed that CHN1 was an independent prognostic factor for DLBCL. Additionally, GSEA and CIBERSORT indicated that CHN1 was correlated with cell adhesion and T cell immune infiltration.

Conclusion: Our data indicate for the first time that high CHN1 expression is associated with favorable outcomes in DLBCL patients, suggesting its potential utility as a prognostic marker in DLBCL.

Keywords: CHN1; biomarker; diffuse large B-cell lymphoma; prognosis.

Figure 1

Study workflow. DEGs, differentially expressed genes; FC, fold change.

Figure 2

Identification and validation of DEGs related to lymphoma aggressiveness. (A) Heatmap of 38 DEGs in the discovery cohort (GSE132929). (B) Heatmap of 15 DEGs in the testing cohorts. Each column represents a sample, and each row represents the gene expression level. Low expression is marked in blue, and high expression is marked in red.

Figure 3

The prognostic significance of CHN1, CD3D, CLU, ICOS, KLRB1 and LAT in DLBCL. Kaplan–Meier curves of OS between the high and low expression groups in GSE10846 and GSE117556 stratified by 6 genes: (A, G) stratified by CHN1, (B, H) stratified by CD3D, (C, I) stratified by CLU, (D, J) stratified by ICOS, (E, K) stratified by KLRB1, and (F, L) stratified by LAT. Low expression is marked in blue, and high expression is marked in red. The p-values were calculated using the Log rank test.

Figure 4

The correlation between CHN1 expression and clinical features in GSE10846. (A) Association between clinical features and CHN1 expression. (B, C) Distribution of CHN1 expression in patients stratified by the molecular subtype and ECOG performance status.

Figure 5

The prognostic significance of CHN1 in important clinical subgroups of DLBCL. Kaplan–Meier curves of overall survival (OS) in the high CHN1 expression and low expression groups in GSE10846 and GSE117556 with different DLBCL subtypes (A–D), different stages (F–H), and different IPI scores (I–J).

Figure 6

The potential biological functions of CHN1. (A–D) Enrichment plots from GSEA in GSE10846. Significantly enriched GO terms (A, B) and KEGG pathways (C, D) in the high CHN1 expression group. (E, F) The proportion of immune infiltrating cells in the high CHN1 expression and low expression groups in GSE10846 (E) and GSE117556 (F).