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  • Review Article
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Mechanisms of therapy-related carcinogenesis

Nature Reviews Cancer volume 5, pages 943–955 (2005)Cite this article

Key Points

  • Treatment for a first cancer is associated with a significantly increased risk of developing a second primary cancer compared with the general population. Such cancers are termed 'therapy-related' and can represent a significant source of mortality for cancer survivors.

  • Therapy-related cancers have been reported after structurally and mechanistically diverse treatments, in which the risk of developing these cancers is often dose dependent (such as for radiotherapy and alkylating agents).

  • Molecular, cellular and epidemiological evidence indicates the existence of discrete mechanisms of carcinogenesis. These could involve either direct targeting of crucial transforming genes and relatively short latency of disease onset, or indirect targeting by the acquisition of a predisposing cellular phenotype (genomic instability) in which disease latency is longer.

  • DNA double-strand breaks that are induced by chemotherapeutic topoisomerase inhibitors can lead to translocation of the mixed lineage leukaemia gene, as well as other crucial transforming genes.

  • Chemotherapeutic methylating agents and thiopurines can promote the emergence of cells with dysfunctional DNA-mismatch repair and concomitant genomic instability.

  • Radiotherapy and chemotherapy interact with other factors, such as hormonal status, cigarette smoking and genetic makeup, to modify the risk of developing a second cancer.

  • By understanding the risk factors for developing therapy-related cancers, and the mechanisms by which they develop, we might be able to prevent them or identify patients at high risk who might benefit from surveillance.

Abstract

Therapy-related cancers, defined as second primary cancers that arise as a consequence of chemotherapy and/or radiotherapy, are unusual in that they have a well-defined aetiology. Knowledge of the specific nature of the initiating exposure and exactly when it occurred has made it easier to identify crucial genetic events and to model these in vitro and in vivo. As such, the study of therapy-related cancers has led to the elucidation of discrete mechanisms of carcinogenesis, including DNA double-strand-break-induced gene translocation and genomic instability conferred by loss of DNA repair. Unsurprisingly, some of these mechanisms seem to operate in the development of sporadic cancers.

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Figure 1: Relative risk of developing a therapy-associated cancer after Hodgkin lymphoma.
Figure 2: The one- or two-hit and mutator phenotype models of therapy-related cancer.
Figure 3: DNA topoisomerase cleavage sites and MLL translocation breakpoints in therapy-related leukaemia.
Figure 4: Cellular processing of a chemotherapy-induced O6-methylguanine DNA lesion by MGMT and DNA-MMR.
Figure 5: The role of cell death and proliferation in therapy-related carcinogenesis.
Figure 6: Relative risk of developing a second cancer according to age at diagnosis of primary Hodgkin lymphoma.

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Acknowledgements

J.M.A. acknowledges the support of Leukaemia Research and Yorkshire Cancer Research. We would also like to thank Tracy Lightfoot (Epidemiology and Genetics Unit, University of York) for critically reviewing this manuscript. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics.

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Authors and Affiliations

  1. Department of Biology, Epidemiology and Genetics Unit, University of York, Heslington, YO10 5YW, York, UK

    James M. Allan

  2. Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, 6120 Executive boulevard, Bethesda, 20892-7238, Maryland, USA

    Lois B. Travis

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Correspondence to James M. Allan.

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DATABASES

Entrez Gene

AF4

AF9

BCL2

Cbp

Enl

GAS7

MGMT

MLH1

MSH2

MSH6

MLL

PML

TP53

National Cancer Institute

breast cancer

Hodgkin lymphoma

lung cancer

lymphoid leukaemia

myeloid leukaemia

non-Hodgkin lymphoma

Glossary

RELATIVE RISK

The observed number of cases reported after chemotherapy and/or radiotherapy as a function of the expected number of cases based on established incidence rates in the general population.

ALKYLATING AGENTS

A large group of anticancer agents (for example, cyclophosphamide, procarbazine and cisplatin) that kill cells by the transfer of an alkyl group (for example, methyl or chloroethyl groups) to DNA, causing inhibition of replication and transcription.

TOPOISOMERASE INHIBITORS

Chemotherapeutic topoisomerase inhibitors (for example, etoposide and doxorubicin) prevent the re-ligation of enzyme-induced DNA double-strand breaks by stabilizing complex formation between the protein and its DNA substrate.

ANTI-METABOLITES

Anti-metabolite anticancer agents (for example, 6-thioguanine) share structural similarities with naturally occurring compounds, including nucleotides, and can be incorporated into DNA or RNA, causing inhibition of cell proliferation.

ABSOLUTE EXCESS RISK

Used as a measure of the actual number of excess cancers owing to previous therapy occurring in a defined population; usually expressed as a function of person-years of follow-up.

CLASTOGENIC

A substance or process that causes chromosome damage such as breaks, duplications or deletions.

DNA-MISMATCH REPAIR

(DNA-MMR). Protects against mutation by correcting base-misinsertion errors made by DNA polymerases during replication. Loss of DNA-MMR confers a mutator phenotype, with microsatellite instability being one component of this.

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Allan, J., Travis, L. Mechanisms of therapy-related carcinogenesis. Nat Rev Cancer 5, 943–955 (2005). https://doi.org/10.1038/nrc1749

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