突变特征代表了肿瘤进化过程中内源性和外源性突变过程的基因组足迹。然而，它们对蛋白质组的功能影响仍不完全清楚。我们分析了来自 18 种癌症类型的 12,341 个癌症基因组中单碱基替换 (SBS) 特征的蛋白质编码影响。停止增益突变 (SGM)（即无义突变）在吸烟、APOBEC 胞苷脱氨酶和活性氧的 SBS 特征中高度丰富。这些突变过程改变了特定的三核苷酸背景，从而用终止密码子取代丝氨酸和谷氨酸。 SGM 经常影响癌症标志通路和肿瘤抑制因子，例如 TP53、FAT1 和 APC。肺癌中烟草驱动的 SGM 与吸烟史相关，并强调了这些有害突变的可预防决定因素。 APOBEC 驱动的 SGM 富含 YTCA 基序，并与 APOBEC3A 表达相关。我们的研究揭示了 SGM 扩展是一种遗传机制，内源性和致癌突变过程直接导致蛋白质功能丧失、肿瘤发生和肿瘤异质性。

Mutational signatures represent a genomic footprint of endogenous and exogenous mutational processes through tumor evolution. However, their functional impact on the proteome remains incompletely understood. We analyzed the protein-coding impact of single-base substitution (SBS) signatures in 12,341 cancer genomes from 18 cancer types. Stop-gain mutations (SGMs) (i.e., nonsense mutations) were strongly enriched in SBS signatures of tobacco smoking, APOBEC cytidine deaminases, and reactive oxygen species. These mutational processes alter specific trinucleotide contexts and thereby substitute serines and glutamic acids with stop codons. SGMs frequently affect cancer hallmark pathways and tumor suppressors such as TP53, FAT1, and APC. Tobacco-driven SGMs in lung cancer correlate with smoking history and highlight a preventable determinant of these harmful mutations. APOBEC-driven SGMs are enriched in YTCA motifs and associate with APOBEC3A expression. Our study exposes SGM expansion as a genetic mechanism by which endogenous and carcinogenic mutational processes directly contribute to protein loss of function, oncogenesis, and tumor heterogeneity.