Abstract
Chemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues, thus influencing their evolution. However, their contributions to the mutation burden and clonal expansions of healthy somatic tissues are not clear. Here, exploiting the mutational footprint of some chemotherapies, we explore their influence on the evolution of hematopoietic cells. Cells of Acute Myeloid Leukemia (AML) secondary to treatment with platinum-based drugs show the mutational footprint of these drugs, indicating that non-malignant blood cells receive chemotherapy mutations. No trace of the 5-fluorouracil (5FU) mutational signature is found in AMLs secondary to exposure to 5FU, suggesting that cells establishing the leukemia could be quiescent during treatment. Using the platinum-based mutational signature as a barcode, we determine that the clonal expansion originating the secondary AMLs begins after the start of the cytotoxic treatment. Its absence in clonal hematopoiesis cases is consistent with the start of the clonal expansion predating the exposure to platinum-based drugs.
Highlights
Chemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues, influencing their evolution
We and others have previously observed that certain chemotherapies, through direct DNA damage or interference with the replication machinery leave a mutational footprint in the metastatic tumors of patients exposed to them as part of the cancer treatment[5,7]
We reasoned that such chemotherapies, being systemic, may be able to leave their mutational footprint in non-malignant cells
Summary
Chemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues, influencing their evolution. The timing of the clonal expansion that causes treatment-related CH or treatment-related AML with respect to the exposure to chemotherapy remains elusive This is key to understanding whether the cytotoxic agent may be the cause of this clonal expansion or only provides a new evolutionary constraint that favors the expansion of a preexisting clone. We used this footprint as a barcode[23] to determine whether the clonal expansion started before or after the beginning of the exposure to the drug This allowed us to study how chemotherapies interfere with healthy hematopoiesis, causing the emergence of treatment-related AML (tAML) or treatment-related CH (tCH)
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