The extent to which exogenous sources, including cancer treatment, contribute to somatic evolution in normal tissue remains unclear. Here we used high-depth duplex sequencing1 (more than 30,000× coverage) to analyse 168 cancer-free samples representing 16 organs from 22 patients with metastatic cancer enroled in the PEACE research autopsy study. In every sample, we identified somatic mutations (range 305–2,854 mutations) at low variant allele frequencies (median 0.0000323). We extracted 16 distinct single-base substitution mutational signatures, reflecting processes that have moulded the genomes of normal cells. We identified alcohol-induced mutation acquisition in liver, smoking-induced mutagenesis in lung and cardiac tissue, and multiple treatment-induced processes, which correlated with therapy type and duration. Exogenous sources, including treatment, underpinned, on average, more than 40% of mutations in liver but less than 10% of mutations in brain samples. Finally, we observed tissue-specific selection, with positive selection in tissues such as lung (PTEN and PIK3CA), liver (NF2L2) and spleen (BRAF and NOTCH2), and limited selection in others, such as brain and cardiac tissue. More than 25% of driver mutations in normal tissue exposed to systemic anti-cancer therapy, including in TP53, could be attributed to treatment. Immunotherapy, although not associated with increased mutagenesis, was linked to driver mutations in PPM1D and TP53, illustrating how non-mutagenic treatment can sculpt somatic evolution. Our study reveals the rich tapestry of mutational processes and driver mutations in normal tissue, and the profound effect of lifetime exposures, including cancer treatment, on somatic evolution.
外源性因素（包括癌症治疗）对正常组织体细胞进化的影响程度尚不明确。本研究采用高深度双链测序技术（覆盖深度超过30000×），对纳入PEACE研究尸检项目的22例转移性癌症患者的168份正常组织样本（涵盖16种器官）进行分析。在所有样本中，我们均检测到体细胞突变（范围305-2854个突变），其变异等位基因频率中位值为0.0000323。通过提取16种不同的单碱基替换突变特征，揭示了塑造正常细胞基因组的生物学过程：在肝脏中观察到酒精诱导的突变累积，肺和心脏组织中发现吸烟引发的突变过程，以及多种与治疗类型和持续时间相关的治疗诱导性突变过程。平均而言，外源性因素（含治疗相关因素）导致了肝脏中超过40%的突变，但在脑部样本中仅占不足10%。此外，我们观察到组织特异性选择现象：肺组织（PTEN和PIK3CA）、肝脏（NF2L2）和脾脏（BRAF和NOTCH2）呈现正向选择，而脑和心肌组织选择作用有限。在接受全身性抗癌治疗（包括TP53突变）的正常组织中，超过25%的驱动基因突变可归因于治疗。尽管免疫治疗与突变增加无显著关联，但其与PPM1D和TP53驱动基因突变有关，揭示了非突变性治疗对体细胞进化的塑造作用。本研究揭示了正常组织中突变过程与驱动基因突变的复杂图景，以及包括癌症治疗在内的终生暴露对体细胞进化的深远影响。
Somatic evolution following cancer treatment in normal tissue
肿瘤(癌症)患者之家