Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Centro de Investigación Biomédica en Red en Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.
PLoS Genet. 2023 Feb 13;19(2):e1010634. doi: 10.1371/journal.pgen.1010634. eCollection 2023 Feb.
Recently, distinct mutational footprints observed in metastatic tumors, secondary malignancies and normal human tissues have been demonstrated to be caused by the exposure to several chemotherapeutic drugs. These characteristic mutations originate from specific lesions caused by these chemicals to the DNA of exposed cells. However, it is unknown whether the exposure to these chemotherapies leads to a specific footprint of larger chromosomal aberrations. Here, we address this question exploiting whole genome sequencing data of metastatic tumors obtained from patients exposed to different chemotherapeutic drugs. As a result, we discovered a specific copy number footprint across tumors from patients previously exposed to platinum-based therapies. This footprint is characterized by a significant increase in the number of chromosomal fragments of copy number 1-4 and size smaller than 10 Mb in exposed tumors with respect to their unexposed counterparts (median 14-387% greater across tumor types). The number of chromosomal fragments characteristic of the platinum-associated CN footprint increases significantly with the activity of the well known platinum-related footprint of single nucleotide variants across exposed tumors.
最近，研究表明，转移性肿瘤、继发性恶性肿瘤和正常人体组织中观察到的独特突变足迹是由接触多种化疗药物引起的。这些特征性突变源自于这些化学物质对暴露细胞的 DNA 造成的特定损伤。然而，目前尚不清楚接触这些化疗药物是否会导致更大染色体畸变的特定足迹。在这里，我们利用从接触过不同化疗药物的患者中获得的转移性肿瘤的全基因组测序数据来解决这个问题。结果，我们在先前接触过铂类治疗的患者的肿瘤中发现了一种特定的拷贝数足迹。与未暴露的肿瘤相比，这种足迹的特征是拷贝数为 1-4 的染色体片段数量显著增加，且大小小于 10Mb（在肿瘤类型中中位数增加 14-387%）。与未暴露肿瘤相比，特征性的铂相关 CN 足迹的染色体片段数量在暴露肿瘤中随着众所周知的与铂相关的单核苷酸变异的足迹活性显著增加。
