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Cancer pharmacogenetics: polymorphisms, pathways and beyond

Key Points

  • The field of pharmacogenetics attempts to use genetic information to predict an individual's drug response. It is especially important in cancer chemotherapy given the narrow therapeutic index of these drugs.

  • So far, pharmacogenetic research has largely focused on the effect of single candidate polymorphisms. However, many of the genetic variants that are associated with extreme drug toxicity are rare and explain only a small portion of the variation seen in drug response.

  • Understanding the interactions of genetic variants within a biological or pharmacological pathway will allow for an improved ability to predict drug response.

  • Folate metabolism — a target of antifolate chemotherapeutic agents and thymidylate-synthase inhibitors — is a biological pathway of substantial interest to pharmacogenetic researchers.

  • Pharmacological pathways are being constructed for the systematic evaluation of the genes that regulate variation in the toxicity and efficacy of anticancer agents.

  • Mouse models show promise in identifying key enzymes in pharmacogenetic pathways and will allow study of genetic variation in these pathways.

Abstract

Inherited genetic variations can affect a patient's response to chemotherapeutic agents given for cancer. Pharmacogenetics aims to use knowledge of these variations to 'tailor' therapy for improved response and reduced toxicity. Most research so far has focused on single polymorphisms. A more comprehensive approach to predict treatment response will be to consider genetic variation in entire biological and pharmacological pathways. Of particular relevance to cancer chemotherapy is folate metabolism, which is the target of methotrexate and 5-fluorouracil. Furthermore, efforts have begun to construct pathways of genes that have pharmacological relevance for individual chemotherapeutic agents. Together, these pathway strategies offer a higher likelihood of achieving the promise of genetically guided cancer therapy.

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Figure 1: Folate metabolism and related pathways.
Figure 2: Possible pathways of irinotecan metabolism.

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Acknowledgements

Support for K. R. was provided by a training grant from the National Cancer Institute. H. M. is supported in part by the National Institute of Health Pharmacogenetics Research Network.

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Correspondence to Cornelia M. Ulrich.

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DATABASES

Cancer.gov

acute lymphocytic leukaemia

acute myelogenous leukaemia

colorectal cancer

LocusLink

ABCB1

CYP2D6

ERCC2

MTHFR

UGT1A1

XRCC1

FURTHER INFORMATION

Pharmacogenetics and Pharmacogenomics Knowledge Base

Pharmacogenetics Research Network, Washington University

Kyoto Encyclopedia of Genes and Genomes

Pharmacogenomics glossary, Cambridge Healthtech Institute

The Mouse Models of Human Cancers Consortium

Glossary

THERAPEUTIC INDEX

The ratio of the median lethal dose to the median effective dose for a given medication. Used to describe the dose range over which a drug has a therapeutic effect without unacceptable toxicity.

POLYMORPHISM

Variation within a gene (often at a single nucleotide) where two or more alleles exist at a frequency of at least 1% in the general population.

FOLATE

One of the B vitamins. The primary role of this B vitamin is as a carrier of methyl groups, especially for purine, pyrimidine and methionine synthesis.

PROBAND

An individual with the condition of interest, who serves as the starting point for exploration of a family pedigree for the genes that are responsible for the condition.

CYTOCHROME-P450 ENZYMES

A family of haem-containing intracellular oxidizing enzymes that are responsible for the first phase of metabolism of many drugs and other ingested toxins.

THYMIDYLATE-SYNTHASE INHIBITORS

A category of chemotherapeutic agents, including 5-fluorouracil, which tightly bind and inhibit the activity of thymidylate synthase, and therefore prevent DNA replication.

MUCOSITIS

Inflammation, irritation and ulceration of the mucosal membranes, especially of the oral cavity and gastrointestinal tract, that occurs as a result of cytotoxic chemotherapy or radiation therapy.

MYELOSUPPRESSION

Suppression of blood-cell formation in the bone marrow.

TRANSCRIPTIONAL-ENHANCER ELEMENT

A region of DNA that might be several thousand base pairs upstream from a given gene's promoter region, but can bind with gene-regulatory proteins and increase the rate of transcription of that gene.

LOSS OF HETEROZYGOSITY

The loss of one allele in a tumour cell for a gene in which the individual is normally heterozygous.

HAZARD RATIO

The comparison of the risk of experiencing an event at any given point in time (hazard) among those with a particular risk factor with those without the risk factor.

GRAFT-VERSUS-HOST DISEASE

A potentially life-threatening condition, which might occur following transplantation of solid organs or haematopoietic cells, in which donor T lymphocytes recognize host cells as foreign and attack host tissues.

ODDS RATIO

A comparison of the risk of experiencing a particular outcome (such as a disease or adverse drug reaction) between two groups of people – one group with a particular risk factor (such as a genotype or a nutrient), and the other group without the risk factor being studied.

TOPOISOMERASE I

An enzyme that creates a transient single-strand break in the phosphodiester backbone of DNA, allowing the strand of DNA to uncoil and rotate freely during replication.

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Ulrich, C., Robien, K. & McLeod, H. Cancer pharmacogenetics: polymorphisms, pathways and beyond. Nat Rev Cancer 3, 912–920 (2003). https://doi.org/10.1038/nrc1233

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