Titin gene mutations enhance radiotherapy efficacy via modulation of tumour immune microenvironment in rectum adenocarcinoma

作者：Hengchang Liu, J. Liu, Xu Guan, Zhixun Zhao, Pu Cheng, Haipeng Chen, Zheng Jiang, Xishan Wang · 发表于：Clinical and Translational Medicine · 年份：2025 · DOI：10.1002/ctm2.70123 · 被引用次数：7 · 研究领域：Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers、Cancer Research and Treatments

Abstract Objective This study investigates the impact of Titin (TTN) gene mutations on radiotherapy sensitivity in rectum adenocarcinoma (READ) by examining changes in the tumour immune microenvironment. Methods Data on gene expression and mutations in READ were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Bioinformatics analysis explored the correlation between TTN mutations and immune cell infiltration. In vitro, lentiviral vectors were used to assess TTN mutations' effects on ANKRD1 expression in two READ cell lines. ANKRD1 was overexpressed, and clonogenic assays evaluated radiotherapy sensitivity. Flow cytometry, immunofluorescence, and comet assays examined mutations' impact on cell cycle, apoptosis, and DNA damage response (DDR). An in vivo mouse model and formalin‐fixed paraffin‐embedded samples from locally advanced rectal cancer (LARC) patients before and after radiotherapy were analyzed, followed by prognostic evaluation. Results Bioinformatics revealed that TTN mutations increase radiation sensitivity in LARC by slowing cell proliferation, promoting apoptosis, and reducing DDR. TTN mutations also inhibit ANKRD1 expression via JUN disruption and enhance CD4/CD8 T‐cell infiltration, improving anti‐tumour immunity and outcomes. Observations from the clinical study showed a substantial decline in ANKRD1 expression levels alongside a notable surge in the counts of CD4 + and CD8 + T cells after undergoing radi...