伦敦大学学院癌症研究所Nicholas McGranahan小组的研究开发出了癌症治疗后正常组织的体细胞进化。相关论文于2025年12月10日发表于国际顶尖学术期刊《自然》杂志上。

在这里，课题组人员采用高深度双工测序（超过3万倍的覆盖范围）来分析来自22名参与PEACE研究尸检研究的转移性癌症患者的168个无癌样本，代表16个器官。在每个样本中，该研究团队发现了低变异等位基因频率（中位数0.0000323）的体细胞突变（范围305-2854个突变）。该课题组研究人员提取了16个不同的单碱基替代突变特征，反映了塑造正常细胞基因组的过程。研究小组发现了肝脏中酒精诱导的突变获得，肺和心脏组织中吸烟诱导的突变，以及多种治疗诱导的过程，这些过程与治疗类型和持续时间相关。包括治疗在内的外源性基因突变平均导致了40%以上的肝脏突变，但不到10%的大脑突变。

最后，小组观察到组织特异性选择，在肺（PTEN和PIK3CA）、肝脏（NF2L2）和脾脏（BRAF和NOTCH2）等组织中存在阳性选择，而在其他组织（如脑组织和心脏组织）中存在有限选择。在接受全身抗癌治疗的正常组织中，超过25%的驱动突变（包括TP53）可归因于治疗。免疫治疗虽然与突变增加无关，但与PPM1D和TP53的驱动突变有关，说明了非诱变治疗如何影响体细胞进化。他们的研究揭示了正常组织中丰富的突变过程和驱动突变，以及包括癌症治疗在内的终身暴露对体细胞进化的深远影响。

据悉，包括癌症治疗在内的外源性药物在多大程度上促进了正常组织的体细胞进化尚不清楚。

附：英文原文

Title: Somatic evolution following cancer treatment in normal tissue

Author: Pich, Oriol, Ward, Sophia, Rowan, Andrew, Naceur-Lombardelli, Cristina, Shutkever, Oliver, Martinez-Ruiz, Carlos, Harries, Sin, Hessey, Sonya, Naidu, Babu, Brenton, James D., Le Quesne, John, Thomas, Anne, Richards, Cathy, Krebs, Matthew G., Turajlic, Samra, Jogai, Sanjay, Zaccaria, Simone, Moore, David, Hiley, Crispin T., Swanton, Charles, Jamal-Hanjani, Mariam, McGranahan, Nicholas

Issue&Volume: 2025-12-10

Abstract: 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.

DOI: 10.1038/s41586-025-09792-4

Source: https://www.nature.com/articles/s41586-025-09792-4