A new genomic study found that many patients previously treated with chemotherapy had elevated somatic mutations and blood cell changes resembling those seen in older adults.
Researchers analyzed blood cell genomes from 23 patients aged 3 to 80 years who had received various chemotherapy drugs for different cancers. These were compared to blood samples from nine healthy patients with no history of chemotherapy. The team focused on hematopoietic stem and progenitor cells (HSPCs) and mature immune cells using whole-genome sequencing.
Seventeen of the 23 chemotherapy-exposed patients had higher-than-expected somatic mutation levels in their HSPCs. Four had more than 1,000 additional single-base substitutions (SBSs), while 13 showed increases of 200 to 600. These mutations formed identifiable patterns—or signatures—linked to specific chemotherapy agents.
Each mutational signature matched a known drug mechanism. For instance, procarbazine, a triazene/hydrazine monofunctional alkylating agent, produced a signature called SBSA. Chlorambucil, bendamustine, and melphalan—nitrogen mustard alkylating agents—produced distinct signatures. Platinum-based drugs like cisplatin and carboplatin generated a pattern similar to SBS31. The antimetabolite 5-fluorouracil caused a separate signature, particularly in lymphoid cells.
Mutation patterns also varied by cell type. Some drugs had greater effects on stem cells and monocytes, while others more heavily impacted T and B lymphocytes. In one case, 5-fluorouracil–associated mutations were found only in lymphoid cells, not in HSPCs or monocytes, suggesting cell-type-specific vulnerability.
Chemotherapy also altered blood cell development. Two patients treated in childhood or early adulthood showed signs of clonal hematopoiesis—multiple expansions of mutated blood stem cell clones with mutations in genes such as PPM1D and TP53. This clonal pattern is usually seen in patients over 70, suggesting chemotherapy may accelerate hematopoietic aging.
The study also compared different drugs within the same class. Oxaliplatin caused fewer mutations than cisplatin or carboplatin, even with extended treatment. Cyclophosphamide induced lower mutation burdens than other nitrogen mustard agents like chlorambucil.
No blood stem cells in exposed patients were completely free of mutations, indicating that chemotherapy affects a wide range of cells. These findings provide insight into the long-term genomic impact of chemotherapy on normal tissues and highlight differences in how various agents alter healthy cells.
Full disclosures can be found in the study.
Source: Nature Genetics
