XAF1 nonsense mutation rs117407731 enhances lung adenocarcinoma susceptibility via apoptosis suppression

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer, the leading cause of global cancer-related mortality. Genetic mutations play critical roles in LUAD pathogenesis. This study aims to investigate the role of XIAP-associated factor 1 (XAF1) rs117407731, a nonsense mutation in certain splice variants (p.22W>*, TGG to TGA), in LUAD susceptibility and cellular function. Genotyping of XAF1 rs117407731 was conducted using blood samples of 103 LUAD patients and 229 healthy individuals. Multivariate logistic regression analysis was carried out to identify independent factors associated with LUAD risk. Immunofluorescence staining showed the expression of XAF1 and XIAP in LUAD tissues. TUNEL staining was employed for cell apoptosis analysis in patient LUAD tissues or mouse tumors. A549 cells were transduced with lentiviral vectors carrying wild-type or mutant XAF1 (XAF1-WT or XAF1-MUT) for functional experiments. XAF1 rs117407731 significantly increased susceptibility to LUAD. XAF1 protein expression was reduced, XIAP expression was elevated, and cell apoptosis was decreased in LUAD tissues from rs117407731 carriers. Overexpressing XAF1-MUT abated XAF1-mediated impairment of A549 cell proliferation and enhancement of apoptosis in vitro. XAF1-MUT overexpression impaired tumor suppression in the xenograft mouse model. XAF1 rs117407731 contributes to LUAD risk by impairing XAF1-mediated apoptosis.