Abstract 2183: <i>DNAH</i> mutations as a potential biomarker for immune checkpoint inhibitor response and survival

Abstract Introduction: The integration of immune checkpoint inhibitors (ICIs) with precision medicine offers a promising avenue for personalized therapies through the identification of biomarkers that predict clinical response and prognosis. However, existing biomarkers have shown limited predictive power, underscoring the need for continued research. Methods: We analyzed whole-exome sequencing data from 342 melanoma patients treated with ICIs to identify genetic determinants of ICI response and survival. Two external cohorts were used to validate findings and explore underlying mechanisms: a non-small cell lung cancer cohort (N=91) and The Cancer Genomic Atlas pan-cancer cohort (N=942). Results: Responders, defined as patients who achieved a complete or partial response to ICIs, were more likely to have received anti-PD-1 therapy compared to anti-CTLA-4 and had higher tumor mutation burden (both P&amp;lt;0.001). All 13 dynein axonemal heavy chain (DNAH) family genes were detected, with DNAH2 (P=0.03), DNAH6 (P&amp;lt;0.001), and DNAH9 (P&amp;lt;0.01) more prevalent in responders. Five DNAH mutations were markedly associated with overall survival (OS), including DNAH2 (hazard ratio [HR]: 0.66; 95% confidence interval [CI]: 0.44-0.98; P=0.039), DNAH6 (HR: 0.48; 95% CI: 0.32-0.73; P&amp;lt;0.001), DNAH9 (HR: 0.64; 95% CI: 0.46-0.90; P=0.009), DNAH5 (HR: 0.67; 95% CI: 0.51-0.90; P=0.006), and DNAH12 (HR: 0.57; 95% CI: 0.36-0.92; P=0.019). Only DNAH6 mutations were associated with longer progression-free survival (PFS) (HR: 0.54; 95% CI: 0.36-0.80; P=0.002). Notably, DNAH2, DNAH6, and DNAH9 mutations (collectively referred to as DNAH-altered) were more frequent in responders and significantly associated with longer PFS (HR: 0.69; 95% CI: 0.51-0.92; P=0.013) and OS (HR: 0.58; 95% CI: 0.43-0.78; P&amp;lt;0.001). These prognostic associations were consistently observed in the validation cohort (HR: 0.28; 95% CI: 0.12-0.61; P&amp;lt;0.001). Multivariate analysis identified DNAH mutations as the most significant predictor of improved OS (HR: 0.56; 95% CI: 0.42-0.76; P&amp;lt;0.001), independent of sex, distant metastases, treatment regimen, and BRAF V600E mutations. Functional analysis showed upregulation of chemokine signaling, cytokine-cytokine receptor interaction, cell cycle regulation, and p53 signaling in DNAH-altered melanomas, which were independently validated in the TCGA cohort. Immune-related signatures, including those implicated in interferon signaling, cytolytic activity, T-cell function, and immune checkpoint regulation, were also enriched in DNAH-altered tumors. Conclusions: This study is the first to identify DNAH mutations as a potential biomarker for predicting ICI response and patient survival. These findings, initially observed in melanoma, may have broader implications for guiding personalized immunotherapy in other cancers. Citation Format: Song Wang, Haimeng Tang, Xue Wu, Qiuxiang Ou. DNAH mutations as a potential biomarker for immune checkpoint inhibitor response and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2183.