Chemotherapy is a systemic treatment designed to eliminate cancer cells by interfering with their ability to grow and divide. This strategy exploits the rapid division rate of cancer cells. Since cell division requires accurately copying the genetic blueprint, many chemotherapy drugs are specifically engineered to damage or alter the structure of deoxyribonucleic acid (DNA). This confirms that chemotherapy does change DNA. The mechanisms of these genetic changes are complex, and the resulting alterations have different implications depending on whether they occur in non-reproductive body cells (somatic) or in sperm and egg cells (germline).
Mechanisms of DNA Alteration
Different classes of chemotherapeutic agents employ distinct chemical strategies to damage the DNA molecule.
Alkylating Agents
Alkylating agents, such as cyclophosphamide, add an alkyl group to DNA bases, often at the N7 position of guanine. This modification creates cross-links, which are covalent bonds, either between the two strands of the DNA helix (inter-strand) or within a single strand (intra-strand). The resulting distorted structure prevents the DNA from being properly unwound for replication or transcription, leading to cell death.
Antimetabolites
Antimetabolites, like fluorouracil, mimic the natural building blocks of DNA or RNA, known as nucleotides. When a cell attempts to synthesize new DNA for division, it mistakenly incorporates these false bases. This misincorporation causes immediate DNA dysfunction and triggers widespread DNA repair attempts that cannot be completed correctly, causing the cell to enter a state of DNA stress.
Intercalators and Topoisomerase Inhibitors
A third group, including antitumor antibiotics such as doxorubicin, functions as DNA intercalators. These flat molecules slip directly between the base pairs of the DNA helix, physically wedging the structure apart. Other drugs, such as topoisomerase inhibitors, prevent essential enzymes from repairing the double-strand breaks they create, effectively cleaving the nucleic acid chains.
Genetic Changes in Somatic Cells
Chemotherapy-induced DNA damage affects any rapidly dividing cell in the body, including those in the bone marrow, hair follicles, and digestive tract. For most somatic cells (non-reproductive body cells), this damage is either lethal, causing temporary side effects like hair loss and myelosuppression, or it is successfully repaired. However, the DNA repair machinery is imperfect, and some damaged cells survive with permanent genetic changes.
These surviving cells carry mutations, a condition known as mutagenicity, which can have long-term health consequences. The primary concern is the link between chemotherapy-induced DNA damage and the development of secondary cancers, specifically therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML). The risk is associated with the type of drug used and the total dose received.
Alkylating agents typically cause t-AML presenting with abnormalities in chromosomes 5 and 7, often appearing five to seven years after treatment. Conversely, Topoisomerase II inhibitors are associated with t-AML involving specific chromosomal translocations, such as those affecting the KMT2A gene, with a shorter latency period of one to three years. Although the cumulative incidence for t-AML is generally low (less than 1% at ten years for most solid tumors), this risk results from permanent genetic damage inflicted on healthy bone marrow stem cells.
Impact on Germline Cells and Heredity
DNA alteration also affects germline cells (sperm and egg cells), raising questions about passing genetic changes to offspring. The most common reproductive consequence is temporary or permanent infertility, resulting from the death of germline stem cells or damage to developing sperm or eggs.
The risk of inheriting de novo mutations (new mutations not present in the parents) appears less straightforward in human studies compared to laboratory models. Some research has identified cases of germline hypermutation in fathers following treatment with specific agents, such as platinum-based drugs and certain alkylating agents. However, large-scale studies of children conceived by cancer survivors who received chemotherapy have not consistently shown an elevated rate of inherited mutations.
Given this complex risk profile, pre-treatment genetic counseling is relevant for patients who wish to have children. Specialists can address the specific risks associated with prescribed drugs and explore mitigation options. Methods such as sperm banking or egg freezing before treatment are offered to preserve healthy germline cells that have not been exposed to the drugs.