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Background: The dynein axonemal heavy chain (DNAH) family of genes encode the dynein axonemal heavy chain, which is involved in cell motility. Genomic variations of DNAH family members have been frequently reported in diverse kinds of malignant tumors. In this study, we analyzed the genomic database to evaluate the mutation status of DNAH genes in gastric adenocarcinoma and further identified the significance of mutant DNAH genes as effective molecular biomarkers for predicting chemotherapy response in gastric cancer patients.Methods: We analyzed the clinical and genomic data of gastric cancer patients published in The Cancer Genome Atlas (TCGA) project. Data on chemotherapy response, overall survival (OS) and chemotherapy-free survival were retrieved. Then, we verified the results via targeted sequencing of gastric cancer patients with similar clinical characteristics but different chemotherapeutic outcomes.Results: In total, 132 gastric adenocarcinoma patients undergoing chemotherapy treatment from TCGA were included in our study. Somatic mutations in all 13 members of the DNAH family of genes were associated with different chemotherapy responses. Compared with patients with wild-type DNAH genes (n = 59), a significantly higher proportion of those with mutations in DNAH genes (n = 73) (55.9% vs 80.8%) responded to chemotherapy (P = 0.002). Moreover, DNAH mutations were correlated with significantly better OS (P = 0.027), chemotherapy-free survival (P = 0.027), fluoropyrimidine-free survival (P = 0.048) and platinum-free survival (P = 0.014). DNAH mutation status was an independent risk factor for OS (P = 0.015), chemotherapy-free survival (P = 0.015) and platinum-free survival (P = 0.011). We identified somatic mutations in 27 (42.2%) of the 64 stage III gastric adenocarcinoma patients receiving fluoropyrimidine-based chemotherapy by targeted exon sequencing with strict screening conditions. In our own cohort, a significantly higher proportion of patients (n = 32) with DNAH mutations than patients with wild-type DNAH genes (n = 32) had a good prognosis (OS > 48 months) (70.4% vs 35.1%) (P = 0.005).Conclusions: Dynein axonemal heavy chain gene mutations contribute positively to chemotherapy sensitivity in gastric cancer patients. [ABSTRACT FROM AUTHOR]