既往治疗定义儿童癌症复发时的突变特征
既往治疗定义儿童癌症复发时的突变特征
作者： 小柯机器人 发布时间：2026/7/23 17:20:17
本期文章：《自然》：Online/在线发表
加拿大多伦多市病童医院Adam Shlien团队近日取得一项新成果。经过不懈努力，他们研究出既往治疗定义儿童癌症复发时的突变特征。该项研究成果发表在2026年7月22日出版的《自然》上。
在这里，课题组研究人员利用突变特征，对一个多机构队列中进行了全基因组测序的肿瘤进行了测量，该队列的治疗剂量和总暴露量均被统一收集。化疗和放疗是复发儿童肿瘤唯一的外源诱变剂，往往是DNA改变的主要原因。与未经治疗的肿瘤相比，治疗后癌症携带的私享突变特征数量接近三倍，体细胞突变总负荷达到两倍。此外，不同化疗的致突变作用也各不相同。
基于铂的治疗，该研究组将相关特征的数量增加了一倍以上，导致大多数患者的变异数量最多。使用治疗暴露日期来跟踪治疗相关突变何时可检测到，该课题组定义了铂相关突变出现的最低阈值。值得注意的是，超过三分之一用铂类药物治疗的肿瘤在一年内显示出可检测的铂特征。这项工作为化疗在儿童癌症中的关键致突变作用提供了基因组证据，作为肿瘤进化的特定驱动因素。这些数据突出了减少治疗升级的机会，以及在扩大之前跟踪耐药克隆的未来可能性。
据悉，患有癌症的儿童在治疗过程中会产生许多短期和长期的副作用，但与化疗有关的DNA损伤程度尚不清楚。
附：英文原文
Title: Prior therapy defines mutation profiles in childhood cancer at relapse
Author: Layeghifard, Mehdi, Daz-Gay, Marcos, Bergstrom, Erik N., Mahendralingam, Mathepan J., Light, Nicholas, Blay, Sasha, Nash, Joshua O., Anderson, Nathaniel D., Au, Jessica N., Davidson, Scott, Ballester, Pedro L., Wen, Timmy, Daud, Syed Kashif, Edward, Lisa-Monique, Ashiqul Islam, S. M., Khandekar, Azhar, Otlu, Burak, Brunga, Ledia, Hammad, Rawan, Nassif, Shimaa, Thacker, Nirav H., Feltham, Tara, Fuentes-Bolanos, Noemi A., Wong-Erasmus, Marie, Levine, Max F., Miller, Katherine E., Shukla, Neerav N., Kinnaman, Michael D., Glodzik, Dominik, Portwine, Carol, Millson, Sabrina, Zorzi, Alexandra P., Mikhail, Mariam, Fernandez, Conrad V., Wheaton, Laura, Gundem, Gunes, Kung, Andrew L., Tabori, Uri, Mayoh, Chelsea, Papaemmanuil, Elli, Cowley, Mark J., Malkin, David, Villani, Anita, Alexandrov, Ludmil B., Shlien, Adam
Issue&Volume: 2026-07-22
Abstract: Children with cancer develop many short- and long-term side-effects of treatment1, but the amount of DNA damage associated with chemotherapy exposure is unclear2. Here we used mutational signatures to measure this damage using whole-genome-sequenced tumours from a multi-institutional cohort for which therapy dose and total exposure were uniformly collected3,4,5. Chemotherapy and radiotherapy were the only exogenous mutagens in relapsed childhood tumours and were often the dominant source of DNA alteration. Compared with treatment-naive tumours, post-therapy cancers carried nearly three times the number of private signatures, and two times the total burden of somatic mutations. Further, the mutagenic effects of different chemotherapies varied. Platinum-based therapies, for which we more than doubled the number of associated signatures, led to the highest number of variants in most patients. Using therapy exposure dates to track when therapy-associated mutations become detectable, we defined a minimum threshold for platinum-associated mutations to emerge. Remarkably, more than one-third of tumours treated with platinum drugs displayed detectable platinum signatures within one year. This work provides genomic evidence for the critical mutagenic effects of chemotherapy in childhood cancer, as a specific driver of tumour evolution. These data highlight opportunities for treatment de-escalation and the future possibility of tracking resistant clones before expansion.
DOI: 10.1038/s41586-026-10803-1
Source: https://www.nature.com/articles/s41586-026-10803-1