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Updated: Aug 10, 2025
Assessing Specificity of Anticancer Drugs In Vitro
Published on: March 23, 2016
Copy number footprints of platinum-based anticancer therapies
Santiago Gonzalez1, Nuria Lopez-Bigas1,2,3, Abel Gonzalez-Perez1,2
1Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
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.
Insights
Chemotherapy, specifically platinum-based drugs, creates a unique DNA copy number (CN) footprint in tumors. This footprint involves more small chromosomal fragments, correlating with known platinum-induced genetic mutations.
Area of Science:
- Genomics
- Cancer Biology
- Pharmacology
Background:
- Chemotherapeutic drugs leave distinct mutational footprints in DNA.
- Previous research identified specific DNA lesions caused by chemotherapies.
- The impact of chemotherapy on larger chromosomal aberrations remained largely unknown.
Purpose of the Study:
- To investigate if chemotherapy exposure results in a specific footprint of chromosomal aberrations.
- To analyze whole genome sequencing data from metastatic tumors in patients exposed to chemotherapy.
- To identify unique copy number alterations associated with specific chemotherapeutic agents.
Main Methods:
- Utilized whole genome sequencing data from metastatic tumors.
- Compared tumors from patients exposed to different chemotherapeutic drugs with unexposed counterparts.
- Analyzed copy number alterations (CNAs) and their characteristics (size, copy number).
Main Results:
- Discovered a specific copy number (CN) footprint in tumors from patients exposed to platinum-based therapies.
- This footprint is characterized by an increased number of chromosomal fragments (copy number 1-4, size <10 Mb).
- The platinum-associated CN footprint significantly correlates with the known platinum-related single nucleotide variant footprint.
Conclusions:
- Platinum-based chemotherapies induce a distinct copy number aberration signature in tumors.
- This signature involves an increase in small chromosomal fragments.
- The CN footprint provides further evidence of chemotherapy's impact on genome stability.
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