Comprehensive Analysis of Gene Expression Profiling to Explore Predictive Markers for Eradication Therapy Efficacy against Helicobacter pylori-Negative Gastric MALT Lymphoma

SIMPLE SUMMARY: In API2-MALT1-positive gastric mucosa-associated lymphoid tissue (MALT) lymphoma, eradication therapy is known to be ineffective. Among API2-MALT1-negative cases, eradication therapy is effective for Helicobacter pylori (Hp)-positive cases and partially effective for Hp-negative cases. Herein, we explored predictive markers for eradication therapy efficacy in cases that were negative for both API2-MALT1 and Hp. Among 164 gastric MALT lymphoma patients, 36 were negative for both API2-MALT1 and Hp. We divided cases of MALT lymphoma negative for both API2-MALT1 and Hp into complete-response (CR) and no-change (NC) groups based on eradication therapy efficacy and conducted comprehensive gene expression analysis. Pathway analysis showed that cancer- and infection-related genes were highly expressed in the NC and CR groups, respectively. Sixteen candidate genes for predictive markers were extracted and validated with real-time PCR. Olfactomedin-4 and Nanog homeobox were positive and negative predictive factors, respectively, for eradication therapy efficacy against gastric MALT lymphoma; they were negative for both API2-MALT1 and Hp. ABSTRACT: Although radiotherapy is the standard treatment for Helicobacter pylori (Hp)-negative gastric mucosa-associated lymphoid tissue (MALT) lymphoma, eradication therapy using antibiotics and an acid secretion suppressor can sometimes induce complete remission. We explored predictive markers for the response to eradication therapy for gastric MALT lymphoma that were negative for both API2-MALT1 and Hp infection using comprehensive RNA sequence analysis. Among 164 gastric MALT lymphoma patients who underwent eradication therapy as primary treatment, 36 were negative for both the API2-MALT1 fusion gene and Hp infection. Based on eradication therapy efficacy, two groups were established: complete response (CR) and no change (NC). The Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that cancer-related genes and infection-related genes were highly expressed in the NC and CR groups, respectively. Based on this finding and transcription factor, gene ontology enrichment, and protein–protein interaction analyses, we selected 16 candidate genes for predicting eradication therapy efficacy. Real-time PCR validation in 36 Hp-negative patients showed significantly higher expression of olfactomedin-4 (OLFM4) and the Nanog homeobox (NANOG) in the CR and NC groups, respectively. OLFM4 and NANOG could be positive and negative predictive markers, respectively, for eradication therapy efficacy against gastric MALT lymphoma that is negative for both API2-MALT1 and Hp infection.