The landscape of non-coding mutations in cancer progression and immune evasion is largely unexplored. Here, we identify transcrptome-wide somatic and germline 3′ untranslated region (3′-UTR) variants from 375 gastric cancer patients from The Cancer Genome Atlas. By performing gene expression quantitative trait loci (eQTL) and immune landscape QTL (ilQTL) analysis, we discover 3′-UTR variants with cis effects on expression and immune landscape phenotypes, such as immune cell infiltration and T cell receptor diversity. Using a massively parallel reporter assay, we distinguish between causal and correlative effects of 3′-UTR eQTLs in immune-related genes. Our approach identifies numerous 3′-UTR eQTLs and ilQTLs, providing a unique resource for the identification of immunotherapeutic targets and biomarkers. A prioritized ilQTL variant signature predicts response to immunotherapy better than standard-of-care PD-L1 expression in independent patient cohorts, showcasing the untapped potential of non-coding mutations in cancer.

癌症进展和免疫逃避中的非编码突变在很大程度上尚未被探索。在这里，我们从癌症基因组图谱中的 375 名胃癌患者中鉴定了转录组范围的体细胞和种系 3' 非翻译区 (3'-UTR) 变异。通过进行基因表达数量性状位点 (eQTL) 和免疫景观 QTL (ilQTL) 分析，我们发现了对表达和免疫景观表型（例如免疫细胞浸润和 T 细胞受体多样性）具有顺式影响的 3'-UTR 变体。使用大规模并行报告分析，我们区分了免疫相关基因中 3'-UTR eQTL 的因果效应和相关效应。我们的方法鉴定了大量 3'-UTR eQTL 和 ilQTL，为免疫治疗靶点和生物标志物的鉴定提供了独特的资源。在独立患者队列中，优先的 ilQTL 变异特征比标准护理 PD-L1 表达更好地预测免疫治疗的反应，展示了癌症中非编码突变的未开发潜力。