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- Title
Copy number footprints of platinum-based anticancer therapies.
- Authors
Gonzalez, Santiago; Lopez-Bigas, Nuria; Gonzalez-Perez, Abel
- Abstract
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. Author summary: Chemotherapies, in conjunction with radiotherapy and surgery still constitute the workhorse of the first line of treatment for many tumor types. Some chemotherapies exert their cytotoxic effect through DNA damage, which results, in many instances, in cell death. Particular types of DNA damage associated with certain chemotherapies lead to specific footprints of single nucleotide variants, which have been identified in tumor and healthy cells of exposed people. Here, we demonstrate that platinum-based chemotherapies also leave a type of larger mutational footprints in the genomes of exposed cells. These consist in an increase of chromosomal fragments of copy number between 1 and 4 and length below 40 Mb, possibly resulting from an increased frequency of double strand breaks in the chromosomes of the cells of exposed patients. This increase in structural variants induced by the exposure to platinum-based chemotherapies may have implications for the evolution of tumors in treated patients, as well as in the long-term side-effects of chemotherapies they may experience, due to damage accumulated in healthy cells.
- Subjects
SINGLE nucleotide polymorphisms; CISPLATIN; WHOLE genome sequencing; CHROMOSOME abnormalities; DNA damage; SECOND harmonic generation; CANCER chemotherapy
- Publication
PLoS Genetics, 2023, Vol 18, Issue 2, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1010634