Key Points
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Germline polymorphisms are known to influence the pharmacokinetics and pharmacological effects of a growing number of anticancer agents.
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Polymorphisms in the human thiopurine methyltransferase (TPMT) gene lead to loss of the functional protein and predispose with high penetrance to severe haematopoietic toxicity in TPMT-deficient patients, unless their dose of mercaptopurine is reduced by 90–95%.
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Candidate-gene strategies have shown that germline polymorphisms in additional genes — such as the glutathione S-transferase genes, the uridine-5′-diphosphate-glucuronosyl-transferase genes and the thymidylate synthetase gene — are associated with the efficacy or toxicity of chemotherapy for acute lymphoblastic leukaemia (ALL).
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Recently, distinct gene-expression profiles of primary ALL cells have been linked to the sensitivity of leukaemia cells to several antileukaemic agents in vitro, and these expression signatures also predicted treatment outcome.
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These findings provide momentum for future genome-wide studies to identify additional genomic determinants of ALL- treatment responses. These will allow the development of polygenic models that can be used to optimize the treatment of ALL and other human cancers.
Abstract
The use of combination chemotherapy to cure acute lymphoblastic leukaemia (ALL) in children emerged in the 1980s as a paradigm for curing any disseminated cancer, and many of the therapeutic principles were subsequently applied to the treatment of other disseminated human cancers. Similarly, elucidation of the pharmacogenomics of ALL and its translation into new chemotherapeutic approaches might serve as a model for optimizing the treatment of other human cancers. Germline polymorphisms and gene-expression patterns in ALL cells have been linked to the toxicity and efficacy of chemotherapy for ALL and are beginning to emerge as useful clinical diagnostics.
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Acknowledgements
This work was supported in part by National Institutes of Health grants and by the American Lebanese Syrian Associated Charities. We would also like to thank C.-H. Pui, M.V. Relling and M. Schwab for helpful discussions; and J.R. Davies for editorial support.
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Glossary
- Pharmacogenomics
-
Often used synonymously with pharmacogenetics, but also used to refer to polygenic strategies within pharmacogenetics.
- Germline polymorphism
-
The existence of two or more variants of a gene locus (alleles, sequence variants or chromosomal structural variants) at significant frequencies (usually >1%) in the population.
- Pharmacogenetics
-
Focuses on the inherited variability in drug targets, target pathways, drug absorption, distribution, metabolism, transport and elimination, or in genes that indirectly influence drug response, and how these genetic variations influence drug-response phenotypes.
- Minimal residual disease
-
Tumour cells remaining in patients after treatment (for example, surgical debulking, chemotherapy or radiotherapy), often at sub-microscopic levels.
- Dose escalation
-
The administration of successively higher doses of drug to a cohort of patients until a subset of these patients experience unacceptable side effects. The highest dose at which patients do not experience serious side effects is the maximum tolerated dose.
- Purine-salvage pathway
-
The synthesis of nucleotides from purine bases, which are recycled to produce the corresponding nucleotides after phosphoribosylation. A key enzyme in this pathway is hypoxanthine-guanine phosphoribosyltransferase.
- ABC transporters
-
Transmembrane proteins that transport a wide variety of substrates (for example, metabolites, lipids, sterols and drugs). Overexpression can lead to drug-resistant cancer. There are 48 known human ABC transporters in 7 distinct subfamilies.
- Penetrance
-
The proportion of individuals who develop a phenotype when they inherit a polymorphism that is associated with this phenotype. If a polymorphism has complete penetrance, the phenotype is present in all carriers, whereas reduced or incomplete penetrance exists if the phenotype is not always present.
- Loss of heterozygosity
-
Loss of one allele in a cell (for example, a tumour cell) of a gene (or chromosomal region) that is heterozygous in normal cells of the same individual.
- Laser-capture microdissection
-
Laser-aided removal of cells from a tissue sample, especially when it consists of different cell types (for example, normal and cancer cells). Individual cells are attached to a transfer film for further analysis.
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Cheok, M., Evans, W. Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy. Nat Rev Cancer 6, 117–129 (2006). https://doi.org/10.1038/nrc1800
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DOI: https://doi.org/10.1038/nrc1800
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