• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of brjclinpharmLink to Publisher's site
Br J Clin Pharmacol. Jul 2006; 62(1): 35–46.
Published online Feb 2, 2006. doi:  10.1111/j.1365-2125.2006.02591.x
PMCID: PMC1885075

The role of pharmacogenetics in cancer therapeutics

Abstract

The variability in treatment responses and narrow therapeutic index of anticancer drugs are some of the key challenges oncologists face. The knowledge of pharmacogenetics can potentially aid in the discovery, development and ultimately individualization of anticancer drugs. The identification of genetic variations that predict for drug response is the first step towards the translation of pharmacogenetics into clinical practice. This review provides an update on the results of studies assessing the effects of germline polymorphisms and somatic mutations on therapeutic outcomes and highlights the potential applications and future challenges in pharmacogenetic research pertaining to cancer therapeutics.

Keywords: cancer therapeutics, chemotherapy, pharmacogenetics, polymorphisms

Introduction

Genetic constitution is an important cause for individual variations in the response and tolerance to drug treatment [1]. These variations are often due to germline mutations in genes that encode for drug-metabolizing enzymes, transporters, cellular targets and signalling pathways. An important distinction between pharmacogenetics in oncology and other therapeutic fields is that somatic mutations, frequently acquired in cancer tissues, also contribute to the variations in treatment outcome and could fortuitously be exploited in targeted therapy to maximize treatment efficacy. The application of pharmacogenetic testing in cancer therapy is particularly attractive because of the narrow therapeutic index of chemotherapeutic agents. This review aims to provide an update on the genetic basis for interindividual variations in therapeutic outcome relevant to key classes of anticancer agents and the potential application of pharmacogenetics in the treatment of cancer.

Drug metabolizing enzymes

Thiopurine methyltransferase and 6-mercaptopurine

Thiopurine methyltransferase (TPMT) is a cytosolic enzyme that catalyses the methylation of aromatic and heterocyclic sulphydryl compounds. The substrates of TPMT include 6-mercaptopurine, 6-thioguanine and azathioprine. 6-mercaptopurine is used for the treatment of childhood acute lymphocytic leukaemia (ALL). Two other pathways compete with TPMT for the metabolism of 6-mercaptopurine: xanthine oxidase converts 6-mercaptopurine to an inactive thiouric acid, whereas hypoxanthine guanine phosphoribosyltransferase converts it to thioinosine monophosphate, the precursor of active thioguanine nucleotides [2]. The xanthine oxidase activity in haematopoietic tissues is negligible and TPMT is the major inactivating enzyme for 6-mercaptopurine in these tissues.

Genetic polymorphisms in TPMT have been associated with 6-mercaptopurine toxicity and therapeutic efficacy [36]. Patients with TPMT deficiency require dose reduction to prevent life-threatening toxicity. Even when treated at 10% of the standard dose of 6-mercaptopurine, patients homozygous for TPMT variants have similar or superior survival compared with patients with at least one wild-type allele [7]. In addition, a higher incidence of etoposide-induced myeloid leukaemia, and radiation-induced brain metastases were observed in patients with TPMT deficiency [8, 9]. It is postulated that increased exposure to thioguanine nucleotides may increase DNA damage and potentiate the leukaemogenic effect of etoposide and radiation. Patients homozygous for the wild-type allele are less likely to have severe treatment toxicity but may be at higher risk of disease relapse [10, 11].

Weinshilboum & Sladek demonstrated that red cell TPMT activity has a trimodal distribution and is inherited in an autosomal codominant fashion [12]. It is estimated that one in 300 caucasians carry two ‘deficient’TPMT alleles (with reduced or no function) and have almost no detectable TPMT activity, while one in 10 has intermediate TPMT activity. At least 21 nonsynonymous mutations have been identified, of which 17 were shown to result in reduced TPMT activity [13, 14]. TPMT*3A is the most common variant in caucasians and, together with TPMT*2 and TPMT*3C, accounts for over 95% of low activity phenotypes. In caucasians, the reported allelic frequencies were 4.4%, 0.4% and 0.2% for TPMT*3A, TPMT 2 and TPMT 3C, respectively [14]. TPMT enzymes produced by TPMT*2, TPMT*3A and TMPT 3C variants were susceptible to proteosomal degradation resulting in lower catalytic activity [15, 16].

There are substantial differences in the frequency of TMPT variants across various population groups. In South-East Asian and African populations, TPMT*3C is the most common TPMT variant. The estimated allele frequencies of TPMT*3C were 2.3–1% and 2.4% for South-East Asian and African populations, respectively [1719]. Variable number tandem repeats (VNTR) have been found in the promoter region of TPMT. Although there is in vitro evidence to suggest that VNTR polymorphisms correlate negatively with TPMT activity, the importance of VNTR polymorphisms has not been clearly established in clinical studies [2022].

The traditional way of assessing TPMT red blood cell activity has several limitations: (i) the test result is unreliable for up to 60 days following blood transfusion, (ii) it is time consuming, and (iii) thiopurine administration may increase enzyme activity by approximately 20%, especially in heterozygous individuals [10, 23]. Recently, a large-scale genotype—phenotype association study has demonstrated the feasibility of pharmacogenetic testing for TPMT polymorphisms (TPMT*2, TPMT*3, TPMT*9, TPMT*16, TMPT*17 and TPMT 18) [14]. A high overall concordance was observed between TPMT genotype and phenotype (98.4%). The sensitivity and specificity of the test were 90% and 99%, respectively, and the positive and negative predictive values were 94% and 99%, respectively. The Food and Drug Administration (FDA) has recommended patients with clinical evidence of severe toxicity, particularly myelosuppression, to be considered for TPMT testing.

UDP-glucuronosyltransferases and irinotecan

UDP-glucuronosyltransferases belong to a superfamily of enzymes that catalyse the glucuronidation of many lipophilic xenobiotics and endogenous substrates. The addition of a glycosyl group from a nucleotide sugar renders hydrophobic compounds more soluble for elimination via bile and urine. The UGT1 gene, located on chromosome 2q37, expresses nine functional UGT1A proteins by alternative splicing of 13 different exons 1 with the common exons 2–5 [24]. UGT1A1 is the major isoform responsible for the glucuronidation of bilirubin and SN-38, the active metabolite of irinotecan [25, 26]. Iyer et al. had reported a wide interindividual variation in UGT1A1 activities, with a 17-fold difference in the rate of SN-38 glucuronidation observed in vitro[27].

Reduced glucuronidation of SN-38 has been associated with increased treatment-related diarrhoea and neutropenia [28, 29]. This observation led to several clinical studies that demonstrated the association between UGT1A1*28, hyperbilirubinaemia and irinotecan toxicity [3033]. UGT1A1*28 homozygosity is associated with Gilbert’s syndrome, a benign form of familial hyperbilirubinaemia [25, 34]. It is defined as a dinucleotide (TA) insertion in the TATA box of the UGT1A1 promoter (TA)7 resulting in a reduction in the expression of UGT1A1 [25, 34, 35]. In one study, grade 4 neutropenia was observed in half of the patients homozygous for UGT1A1*28, whereas no grade 4 toxicity was reported in patients lacking this allele [32]. Based on this study, it is estimated that UGT1A1*28 genotyping could lead to a 50% relative reduction or 5% absolute reduction in grade 4 neutropenia. This translates into the prevention of one severe irinotecan toxicity for every 20 patients genotyped for UGT1A1*28. In the same study, variant −3156G→A also predicted for lower nadir neutrophil counts [32]. This latter polymorphism is common (frequency of 0.3) and in close proximity to the phenobarbital response enhancer module. It is also in linkage disequilibrum with UGT1A1*28 but the functional significance of this polymorphism is still unknown [36].

There is a wide frequency variation in the UGT1A1*28 genotype across different population groups. Homozygosity for UGT1A1*28 occurs in 19–24% of the populations in the Indian subcontinent, 12–27% of African populations, 5–15% of caucasian populations but only 1.2–5% in South-east Asian and Pacific populations [35, 3740]. In addition, several other polymorphisms that are more commonly associated with Gilbert’s syndrome in East Asians were shown to have reduced SN-38 glucuronidation activities in vitro: UGT1A1*60 (3279T→G), UGT1A1*6 (211G→A, G71R), UGT1A1*27 (686C→A, P229Q) and UGT1A1*7 (1456T→G, Y486D) [3641]. The reported allelic frequencies of these variants were 13–23% (UGT1A1*6), 13.6% (UGT1A1*60) and 0.5–2.8% (UGT1A1*27) [4244]. Prospective studies should be performed in order better to ascertain the benefits and optimal genotyping strategy in different population groups.

Dihydropyrimidine dehydrogenase and 5-fluorouracil

5-fluorouracil (5-FU) has been a cornerstone in the treatment of colorectal cancer over the past few decades. 5-FU is converted to its cytotoxic nucleotides, which in turn inhibit thymidylate synthase or incorporates into RNA and DNA. It is metabolized to its inactive form, 5,6-dihydro-5-fluorouracil, by dihydropyrimidine dehydrogenase (DPYD) [45]. DPYD is the rate-limiting enzyme in the catabolism of pyrimidines such as uracil and thymidine, and the synthesis of β-alanine [46]. Decreased DPYD activity can lead to the accumulation of 5-FU and severe toxicities, including mucositis, neutropenia, neurological symptoms and death [4749].

Over 40 different polymorphisms have been reported, of which 17 mutations are found in patients with severe 5-FU toxicity [50]. It is estimated that 3–5% of the population is heterozygous and 0.1% is homozygous for alleles with impaired DPYD function [51, 52]. DPYD*2A is the most common DPYD polymorphism associated with impaired DPYD activity. DPYD*2A is caused by a 5′ splice site mutation at intron 14 G1A resulting in the formation of a truncated protein [53]. It is estimated that about a quarter of patients suffering from severe 5-FU toxicity have DPYD*2A polymorphism [54, 55]. The allelic frequency of DPYD*2A is about 1.8% in European caucasians, while it has not been detectable in Egyptian and Japanese populations [5658].

Although DPYD polymorphisms are associated with severe 5-FU toxicity, about one- to two-thirds of patients who experienced treatment toxicity do not have a molecular basis for DPYD deficiency [59, 60]. In addition, DPYD genotyping correlates poorly with DPYD level [61]. The low frequency of DPYD polymorphisms as well as the low sensitivity and specificity of genotyping hampered the application of DPYD pharmacogenetics to clinical practice.

CYP2D6 and tamoxifen

Tamoxifen is widely used in the treatment for oestrogen receptor-positive breast cancer. It is metabolized by several CYP isoforms (CYP3A, CYP2D6, CYP2C9, CYP2C19, CYP2B6 and CYP1A2) to form several metabolites, including 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen and 4-OH-N-desmethyl-tamoxifen (endoxifen) [62, 63]. Both endoxifen and 4-OH-tamoxifen are 100 times more potent than tamoxifen, but endoxifen is present at a much higher plasma concentration than 4-OH-tamoxifen [64].

CYP2D6 appears to be the predominant CYP isoform that catalyses the formation of endoxifen [63]. There is a strong association between CYP2D6 genotype and plasma levels of endoxifen [65]. A fourfold difference in endoxifen concentration was observed between subjects homozygous for wild type compared with those homozygous for the nonfunctional CYP2D6 variants. Studies assessing the association between CYP2D6 genotype with patient outcomes to tamoxifen have produced contradicting reports. Nowell et al. did not find a significant association between CYP2D6 genotype and overall survival [66], whereas Wegman et al. suggested that tamoxifen treatment benefited patients with CYP2D6*4 alleles but not CYP2D6*1 homozygotes [67]. However, it is difficult to interpret the results of both retrospective studies as the number of patients homozygous for variant CYP2D6 genotype was small and the comparison arms were not controlled for tumour stage and other treatment modalities.

At least 88 allelic variants have been described, many of which are nonfunctional or have reduced catalytic activity. It is estimated that 5–10% of caucasians have nonfunctional variants [68]. CYP2D6*4 is the most common nonfunctioning variant in caucasians and, together with CYP2D6*3, CYP2D6*5 and CYP2D6*6, constitutes approximately 97% of all nonfunctioning phenotypes [69, 70]. In CYP2D6*3 and CYP2D6*6, a single base deletion at 2637A and 1795T, respectively, results in a premature stop codon and the production of a nonfunctioning truncated protein, whereas CYP2D6*5 is a gene deletion. CYP2D6*4 allele has a 1934G→A transition at the junction of the intron 3 and exon 4, producing a splicing defect [71].

Gene duplication is responsible for ultrarapid CYP2D6 metabolism in only 1–3% of Europeans and up to 20% of some Middle-Eastern and North African populations [72]. The frequencies of nonfunctional alleles are relatively low in Asians, but there is a large proportion of the population with variant alleles that are associated with reduced CYP2D6 activity. CYP2D6*10 (188C→T, P34S) occurs in about 50% of East Asians and largely accounts for lower CYP2D6 activity in the extensive metabolizer phenotype in Asians [73, 74], whereas CYP2D6*2 and CYP2D6*17 are more common in African-Americans [75]. Additional studies will be needed to address the impact of gene duplication and reduced function alleles.

Metabolizing enzymes of the folate pathway

Methylenetetrahydrofolate reductase and methotrexate

Methotrexate exerts its cytotoxic effects by inhibiting several folate-dependent enzymes, including dihydrofolate reductase, thymidylate synthase and aminoimidazole carboxamide transformylase. The treatment toxicity from high-dose methotrexate can be minimized with the administration of reduced folate, folinic acid [76]. Conversely, a reduction of intracellular folate pool can lead to an increase in methotrexate toxicity.

5,10-methylenetetrahydrofolate reductase (MTHFR) is an important enzyme that regulates folate and homocysteine homeostasis. It catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and the carbon moiety required for the conversion of homocysteine to methionine [77].

Deficiency in MTHFR has been associated with a reduced folate pool, as well as neurological and vascular diseases [7880]. 677C→T, a common functional polymorphism of MTHFR, produces an alanine to valine amino acid substitution within the predicted catalytic domain of the MTHFR enzyme. The resultant variant protein has reduced catalytic activity and is more thermolabile [81]. An A→C mutation at position 1298 of MTHFR gene abolishes an MboII recognition site. Although 1298A→C has been associated with reduced MTHFR activity, neither the homozygous nor heterozygous state is associated with a change in homocysteine or folate level. However, it appears that individuals heterozygous for both 677C→T and 1298A→C have a phenotype similar to that of 677TT homozygotes [82]. The allelic frequency of 677C→T variant ranges from 24 to 46% in Europeans, 26 to 44% in East Asians, 57% in Mexicans and 11% in African Americans [83, 84].

MTHFR677C→T variant is associated with a decreased folate level [85]. Patients with variant MTHFR677C→T allele are more likely to experience treatment-related toxicity after methotrexate, as part of the regimens for breast cancer, ovarian cancer and bone marrow transplant [8689]. Testing for MTHFR polymorphisms may help to identify individuals at risk of severe treatment toxicity. It is likely that polymorphisms in other folate-dependent enzymes and transporters may also affect the response to methotrexate.

Drug targets

Thymidylate synthase and antimetabolites

Thymidylate synthase (TYMS) catalyses the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), the only source of intracellular thymidylate essential for DNA replication and repair [90]. It is the main target for 5-FU, capecitabine and raltitrexed. The active metabolite of 5-FU, fluorodeoxyuridine monophosphate (FdUMP) blocks the formation of dTMP by forming a stable complex with TYMS. The overexpression of TYMS is associated with resistance to 5-FU and other TYMS inhibitors such as raltitrexed [9193] and reduced response to hepatic artery infusion of floxuridine [94].

TYMS gene contains seven exons and a 5′-flanking untranslated enhancer region containing a 28-bp tandem repeat sequence [95, 96]. The number of tandem repeats varies from two (2R) to nine (9R) copies [97]. The translational efficiency is correlated with the number of tandem repeats. In vitro, there is a 2.6–3.6-fold increase in TYMS expression with the 3R variant compared with the 2R variant [98, 99]. The distribution of tandem repeats in caucasians is 16% 2R/2R, 51–55% 2R/3R, 29–32% 3R/3R and < 1% for other variants [100, 101].

A G→C SNP located at the 12th nucleotide of the second tandem repeat of 3R has recently been identified (3RC) [102]. The polymorphism occurs within the USF consensus element and alters the transcriptional activity of TS gene. 3RC variant has a lower TS expression level and is associated with better clinical outcome with fluoropyrimidines when compared with the 3R variant [103, 104]. This may explain some of the discrepancies seen when 5′ UTR tandem repeats were used alone in predicting 5-FU response. The 3RC allele (3RC) occurs in 56%, 28% and 37% of all 3R alleles in caucasians, African-Americans and Chinese, respectively [102].

In patients with metastatic colorectal cancer, those homozygous for 3R had a poorer survival (12 months vs. 16 months) and a lower response rate (9%vs. 50%) to 5-FU-based chemotherapy [99, 105]. Similarly, patients homozygous for 3R benefited less from 5-FU adjuvant chemotherapy and neoadjuvant chemoradiation [106, 107]. In children with acute lymphoblastic leukaemia who were treated with methotrexate, those homozygous for 3R had poorer event-free survival [108].

Gene amplification can result in the overexpression of TYMS. Wang et al. has shown the feasibility of using fluorescence in situ hybridization to detect TYMS gene amplification in cancer tissues. In this study, patients with metastases containing TYMS amplification had poorer survival (329 vs. 1021 days), which suggests that TYMS amplification is a major mechanism of 5-FU resistance [109].

A 6-bp deletion located in the 3′ untranslated region (UTR), 447 bp downstream of the stop codon, has also been associated with decreased mRNA stability and intratumoral TYMS level [110]. This 3′-UTR polymorphism was found to be in linkage disequilibrium with 5′-flanking untranslated enhancer region polymorphism and the haplotypes 2R/ins 6-bp seemed to be associated with increased treatment toxicity [100]. In colorectal cancer tissues, the loss of heterozygosity (LOH) of the TYMS locus is a common phenomenon (62%) [111]. Patients with 3R/2R genotype can acquire 3R/loss or 2R/loss genotype in their cancer tissues. Patients with tumour 3R/loss genotype had a poorer treatment outcome compared with 2R/loss when treated with fluoropyrimidine-based therapy [112]. This highlights the importance of assessing somatic mutations in cancer tissues in order to predict for treatment outcome.

Epidermal growth factor receptor and tyrosine kinase inhibitors

The epidermal growth factor receptor (EGFR) is frequently dysregulated and overexpressed in a number of epithelial cancers including nonsmall cell lung cancer (NSCLC) and head and neck cancer. EGFR signalling is important for tumour cell proliferation and angiogenesis, and has become an attractive target for therapy [113].

Two oral EGFR tyrosine kinase inhibitors (TKI), gefitinib and erlotinib, have been approved for use as second- or third-line therapy in advanced non-small-cell lung cancer. These drugs have a favourable toxicity profile. The most frequent toxicities are diarrhoea and acneiform rash. Patients who develop skin toxicity are associated with a favourable outcome [114]. After evaluating the initial analysis of two large placebo-controlled phase III trials (BR21 and ISEL), FDA currently limits the use of gefitinib to patients who are already receiving and benefiting from gefitinib [115, 116]. However, studies on gefitinib and EGFR have provided valuable insight into genetic variation and treatment outcomes.

Different population groups showed significant variability in the response to these drugs. The response rate of gefitinib is higher in Japanese patients compared with caucasians (27.5%vs. 10.5%) [117]. Furthermore, the intensity of immunohistochemical staining for tumour EGFR expression does not correlate well with response [118]. Recently, somatic mutations in the tyrosine kinase domain of the EGFR were found to be present in most patients who responded to gefitinib and erlotinib [119121]. It is postulated that these mutations, which cluster around the ATP-binding site of the tyrosine kinase domain (exons 18, 19 and 21), stabilize the interaction between drug and the tyrosine kinase domain. The most common mutations are due to multinucleotide in-frame deletion in exon 19 and a point mutation L858RA in exon 20. Within the tyrosine kinase domain, a point mutation, T790M, seems to confer resistance to gefitinib [122]. Two Asian studies found that EGFR genotyping has a sensitivity of 52–92%, a specificity of 79–91% and a negative predictive value of 86–90%, which construes that nine out of 10 patients with a negative EGFR genotyping will not benefit from gefitinib treatment [123, 124].

In addition to EGFR tyrosine kinase domain mutations, several studies have linked EGFR TKI sensitivity to increased EGFR gene copy number in lung cancer [125, 126]. Cappuzzo et al. have demonstrated that a high EGFR gene copy number was associated with better response (36%vs. 3%) and survival (19 months vs. 7 months) when treated with gefitinib [126].

The potential importance of germline polymorphisms in determining clinical response to TKIs has not been clearly established. However, the presence of interethnic differences in the frequency of somatic mutations, and the positive correlation between rash and response and/or survival when treated with TKIs, may suggest a possible genetic basis for susceptibility to somatic mutation and skin toxicity [114, 117, 127]. Currently, research efforts have been focusing on identifying germline variants that may affect: (i) the cellular susceptibility to somatic mutations, (ii) the development of skin rash, and (iii) the transcriptional activity and expression of EGFR [128130].

Application of pharmacogenetic testing to cancer therapeutics

Currently, there are strong data to support the use of pharmacogenetic testing for UGT1A1 and TPMT polymorphisms. Pharmacogenetic information pertaining to irinotecan toxicity is now included in the revised drug labelling after the FDA advisory committee meeting in November 2004. Pharmacogenetic testing may enable clinicians to identify those patients who are less likely to benefit from expensive drugs, and those who are susceptible to severe treatment-related toxicities at standard treatment doses, thus making treatments safer and more cost-effective. The availability of high-throughput genotyping platforms has allowed a large set of SNP markers to be studied and may lower the cost of pharmacogenetic testing.

The utility of pharmacogenetics extends beyond cancer therapy. It has the potential to facilitate the identification of drug targets and accelerate drug discovery and development. Tumour tissues frequently acquire mutations in oncogenes, which themselves can confer sensitivity to drugs, as in the case of EGFR tyrosine kinase domain mutation and response to gefitinib. Incorporating pharmacogenetic testing in early clinical trials may provide vital information about pharmacogenetic profiles with treatment responses and tolerability. This information can help investigators identify patients with specific pharmacogenetic profiles, and may reduce the size and cost of phase III clinical trials needed to establish drug efficacy.

Future challenges

Early studies of pharmacogenetics were mostly monogenic candidate-gene association studies. These studies were often hypothesis driven, based on identifying phenotypic variability and correlating with genetic polymorphism. Although this approach has been extremely useful in advancing our knowledge in pharmacogenetics, monogenic association study has some limitations: (i) it is difficult to ascertain if the positive association observed could be due to the linkage with untyped functional variant allele or to intra-gene interaction; (ii) it is not often possible to evaluate each SNP directly because of cost constraints and incomplete knowledge of the polymorphisms; and (iii) drug disposition and drug response are usually determined by the interaction of multiple genes and pathways.

As there is approximately one SNP in every 1000–3000 base pairs throughout the human genome [131], it is possible that up to hundreds of different variable loci are present within a candidate gene. However, SNPs or alleles physically close together on the same chromosome are rarely separated by recombination, and hence they tend to occur more frequently together rather than by chance. This association between neighbouring SNPs or alleles is known as linkage equilibrium and it enables the selection of marker SNPs, known as haplotype tagging SNPs, to capture the genetic diversity across a region or haplotypes block, thus reducing the number of SNPs needed to represent all the common polymorphisms in a candidate gene to an average of five to seven SNPs. Recently, Sai et al. reported that the haplotype structure of UGT1A1 in Japanese patients may be adequately represented by limited numbers of marker alleles, which illustrates the economy of this approach. There is emerging evidence that polymorphisms in OATP1B1 and ABCC2 may also affect the disposition of SN-38 [132, 133]. Haplotype association studies would allow the evaluation of the large set of candidate genes, for example, between UGT1A1 and various transporters in association studies. There is an ongoing global effort by the International HapMap Project to establish the haplotype structures of four different population groups. Once the population haplotype structure is available, empirical genome-wide screen can be performed to identify candidate genes with appropriate haplotype tagging SNPs. Expression microarrays and proteomic studies provide alternative strategies to identify candidate genes that will complement current haplotype—phenotype approaches.

Conclusions

Pharmacogenetic studies have provided strong evidence for the genetic basis of drug response and tolerability. The translation of pharmacogenetic research into clinical practice is time consuming, labour intensive and expensive. When possible, pharmacogenetic testing should be incorporated in early phase clinical trials. The biological functions of causal variants should be evaluated and the association validated across different population groups. All of these require a collaborative effort involving multiple disciplines and between academic centres with complementary areas of expertise. The Pharmacogenetics Research Network (PGRN), which comprises 12 institutes across the USA, is an example of one such collaboration (http://www.pharmgkb.org/). Although the extensive use of pretreatment pharmacogenetic testing is still limited, the prospects of using pharmacogenetic testings to tailor individual therapy regimens in the future are promising.

References

1. Vesell ES. Pharmacogenetic perspectives gained from twin and family studies. Pharmacol Ther. 1989;41:535–52. [PubMed]
2. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992;43:329–39. [PubMed]
3. Evans WE, Horner M, Chu YQ, Kalwinsky D, Roberts WM. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr. 1991;119:985–9. [PubMed]
4. Evans WE, Hon YY, Bomgaars L, Coutre S, Holdsworth M, Janco R, Kalwinsky D, Keller F, Khatib Z, Margolin J, Murray J, Quinn J, Ravindranath Y, Ritchey K, Roberts W, Rogers ZR, Schiff D, Steuber C, Tucci F, Kornegay N, Krynetski EY, Relling MV. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol. 2001;19:2293–301. [PubMed]
5. Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, Pui CH, Evans WE. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. 1999;91:2001–8. [PubMed]
6. Lennard L, Van Loon JA, Weinshilboum RM. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther. 1989;46:149–54. [PubMed]
7. Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE. Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood. 1999;93:2817–23. [PubMed]
8. Relling MV, Rubnitz JE, Rivera GK, Boyett JM, Hancock ML, Felix CA, Kun LE, Walter AW, Evans WE, Pui CH. High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet. 1999;354:34–9. [PubMed]
9. Bo J, Schroder H, Kristinsson J, Madsen B, Szumlanski C, Weinshilboum R, Andersen JB, Sshmiegelow K. Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism. Cancer. 1999;86:1080–6. [PubMed]
10. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet. 1990;336:225–9. [PubMed]
11. Stanulla M, Schaeffeler E, Flohr T, Cario G, Schrauder A, Zimmermann M, Welte K, Ludwig WD, Bartram CR, Zanger UM, Eichelbaum M, Schrappe M, Schwab M. Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. JAMA. 2005;293:1485–9. [PubMed]
12. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980;32:651–62. [PMC free article] [PubMed]
13. McLeod HL, Siva C. The thiopurine S-methyltransferase gene locus — implications for clinical pharmacogenomics. Pharmacogenomics. 2002;3:89–98. [PubMed]
14. Schaeffeler E, Fischer C, Brockmeier D, Wernet D, Moerike K, Eichelbaum M, Zanger UM, Schwab M. Comprehensive analysis of thiopurine S-methyltransferase phenotype—genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics. 2004;14:407–17. [PubMed]
15. Tai HL, Fessing MY, Bonten EJ, Yanishevsky Y, d’Azzo A, Krynetski EY, Evans WE. Enhanced proteasomal degradation of mutant human thiopurine S-methyltransferase (TPMT) in mammalian cells: mechanism for TPMT protein deficiency inherited by TPMT*2, TPMT*3A, TPMT*3B or TPMT*3C. Pharmacogenetics. 1999;9:641–50. [PubMed]
16. Tai HL, Krynetski EY, Schuetz EG, Yanishevski Y, Evans WE. Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity. Proc Natl Acad Sci USA. 1997;94:6444–9. [PMC free article] [PubMed]
17. Hon YY, Fessing MY, Pui CH, Relling MV, Krynetski EY, Evans WE. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum Mol Genet. 1999;8:371–6. [PubMed]
18. Collie-Duguid ES, Pritchard SC, Powrie RH, Sludden J, Collier DA, Li T, McLeod HL. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics. 1999;9:37–42. [PubMed]
19. Chang JG, Lee LS, Chen CM, Shih MC, Wu MC, Tsai FJ, Liang DC. Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations. Pharmacogenetics. 2002;12:191–5. [PubMed]
20. Spire-Vayron de la Moureyre C, Debuysere H, Fazio F, Sergent E, Bernard C, Sabbagh N, Marez D, Lo Guidic JM, D’Halluin JC, Broly F. Characterization of a variable number tandem repeat region in the thiopurine S-methyltransferase gene promoter. Pharmacogenetics. 1999;9:189–98. [PubMed]
21. Alves S, Amorim A, Ferreira F, Prata MJ. Influence of the variable number of tandem repeats located in the promoter region of the thiopurine methyltransferase gene on enzymatic activity. Clin Pharmacol Ther. 2001;70:165–74. [PubMed]
22. Marinaki AM, Arenas M, Khan ZH, Lewis CM, Shobowale-Bakre el M, Escuredo E, Fairbanks LD, Mayberry JF, Wicks AC, Ansari A, Sanderson J, Duley JA. Genetic determinants of the thiopurine methyltransferase intermediate activity phenotype in British Asians and Caucasians. Pharmacogenetics. 2003;13:97–105. [PubMed]
23. McLeod HL, Krynetski EY, Wilimas JA, Evans WE. Higher activity of polymorphic thiopurine S-methyltransferase in erythrocytes from neonates compared to adults. Pharmacogenetics. 1995;5:281–6. [PubMed]
24. Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Belanger A, Fournel-Gigleux S, Green M, Hum DW, Iyanagi T, Lancet D, Louisot P, Magdalou J, Chowdhury JR, Ritter JK, Schachter H, Tephly TR, Tipton KF, Nebert DW. The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics. 1997;7:255–69. [PubMed]
25. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP, Chowdhury NR. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med. 1995;333:1171–5. [PubMed]
26. Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest. 1998;101:847–54. [PMC free article] [PubMed]
27. Iyer L, Hall D, Das S, Mortell MA, Ramirez J, Kim S, Di Rienzo A, Ratain MJ. Phenotype—genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther. 1999;65:576–82. [PubMed]
28. Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ. Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res. 1994;54:3723–5. [PubMed]
29. Wasserman E, Myara A, Lokiec F, Goldwasser F, Trivin F, Mahjoubi M, Misset JL, Cvitkovic E. Severe CPT-11 toxicity in patients with Gilbert’s syndrome: two case reports. Ann Oncol. 1997;8:1049–51. [PubMed]
30. Ando Y, Saka H, Asai G, Sugiura S, Shimokata K, Kamataki T. UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan. Ann Oncol. 1998;9:845–7. [PubMed]
31. Iyer L, Das S, Janisch L, Wen M, Ramirez J, Karrison T, Fleming GF, Vokes EE, Schilsky RL, Ratain MJ. UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J. 2002;2:43–7. [PubMed]
32. Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004;22:1382–8. [PubMed]
33. Marcuello E, Altes A, Menoyo A, Del Rio E, Gomez-Pardo M, Baiget M. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer. 2004;91:678–82. [PMC free article] [PubMed]
34. Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert’s syndrome. Lancet. 1996;347:578–81. [PubMed]
35. Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci USA. 1998;95:8170–4. [PMC free article] [PubMed]
36. Innocenti F, Grimsley C, Das S, Ramirez J, Cheng C, Kuttab-Boulos H, Ratain M, Di Rienzo A. Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics. 2002;12:725–33. [PubMed]
37. Premawardhena A, Fisher CA, Fathiu F, de Silva S, Perera W, Peto TE, Olivieri NF, Weatherall DJ. Genetic determinants of jaundice and gallstones in haemoglobin E beta thalassaemia. Lancet. 2001;357:1945–6. [PubMed]
38. Premawardhena A, Fisher CA, Liu YT, Verma IC, de Silva S, Arambepola M, Clegg JB, Weatherall DJ. The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1): hematologic and evolutionary implications. Blood Cells Mol Dis. 2003;31:98–101. [PubMed]
39. Bosma PJ, van der Meer IM, Bakker CT, Hofman A, Paul-Abrahamse M, Witteman JC. UGT1A1*28 allele and coronary heart disease: the Rotterdam Study. Clin Chem. 2003;11:1296–7. [PubMed]
40. Hall D, Ybazeta G, Destro-Bisol G, Petzl-Erler M, Di Rienzo A. Variability at the uridine diphosphate glucuronosyltransferase 1A1 promoter in human populations and primates. Pharmacogenetics. 1999;9:591–9. [PubMed]
41. Jinno H, Tanaka-Kagawa T, Hanioka N, Saeki M, Ishida S, Nishimura T, Ando M, Saito Y, Ozawa S, Sawada J. Glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan (CPT-11), by human UGT1A1 variants, G71R, P229Q, and Y486D. Drug Metab Dispos. 2003;31:108–13. [PubMed]
42. Akaba K, Kimura T, Sasaki A, Tanabe S, Ikegami T, Hashimoto M, Umeda H, Yoshida H, Umetsu K, Chiba H, Yuasa I, Hayasaka K. Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene: a common missense mutation among Japanese, Koreans and Chinese. Biochem Mol Biol Int. 1998;46:21–6. [PubMed]
43. Huang CS, Luo GA, Huang ML, Yu SC, Yang SS. Variations of the bilirubin uridine-diphosphoglucuronosyl transferase 1A1 gene in healthy Taiwanese. Pharmacogenetics. 2000;10:539–44. [PubMed]
44. Sai K, Saeki M, Saito Y, Ozawa S, Katori N, Jinno H, Hasegawa R, Kaniwa N, Sawada J, Komamura K, Ueno K, Kamakura S, Kitakaze M, Kitamura Y, Kamatani N, Minami H, Ohtsu A, Shirao K, Yoshida T, Saijo N. UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer. Clin Pharmacol Ther. 2004;75:501–15. [PubMed]
45. Heggie GD, Sommadossi JP, Cross DS, Huster WJ, Diasio RB. Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res. 1987;47:2203–6. [PubMed]
46. Wasternack C. Degradation of pyrimidines and pyrimidine analogs—pathways and mutual influences. Pharmacol Ther. 1980;8:629–51. [PubMed]
47. Fleming RA, Milano GA, Gaspard MH, Bargnoux PJ, Thyss A, Plagne R, Renee N, Schneider M, Demard F. Dihydropyrimidine dehydrogenase activity in cancer patients. Eur J Cancer. 1993;29A:740–4. [PubMed]
48. Lyss AP, Lilenbaum RC, Harris BE, Diasio RB. Severe 5-fluorouracil toxicity in a patient with decreased dihydropyrimidine dehydrogenase activity. Cancer Invest. 1993;11:239–40. [PubMed]
49. Diasio RB. Clinical implications of dihydropyrimidine dehydrogenase on 5-FU pharmacology. Oncology. 2001;15:21–6. [PubMed]
50. van Kuilenburg AB, Meinsma R, van Gennip AH. Pyrimidine degradation defects and severe 5-fluorouracil toxicity. Nucleosides Nucleotides Nucl Acids. 2004;23:1371–5. [PubMed]
51. Lu Z, Zhang R, Diasio RB. Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res. 1993;53:5433–8. [PubMed]
52. Ridge SA, Sludden J, Wei X, Sapone A, Brown O, Hardy S, Canney P, Fernandez-Salguero P, Gonzalez FJ, Cassidy J, McLeod HL. Dihydropyrimidine dehydrogenase pharmacogenetics in patients with colorectal cancer. Br J Cancer. 1998;77:497–500. [PMC free article] [PubMed]
53. Wei X, McLeod HL, McMurrough J, Gonzalez FJ, Fernandez-Salguero P. Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J Clin Invest. 1996;98:610–5. [PMC free article] [PubMed]
54. Raida M, Schwabe W, Hausler P, Van Kuilenburg AB, Van Gennip AH, Behnke D, Hoffken K. Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5′-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)-related toxicity compared with controls. Clin Cancer Res. 2001;7:2832–9. [PubMed]
55. van Kuilenburg AB, Meinsma R, Zoetekouw L, Van Gennip AH. High prevalence of the IVS14 + 1G→A mutation in the dihydropyrimidine dehydrogenase gene of patients with severe 5-fluorouracil-associated toxicity. Pharmacogenetics. 2002;12:555–8. [PubMed]
56. van Kuilenburg AB, Muller EW, Haasjes J, Meinsma R, Zoetekouw L, Waterham HR, Baas F, Richel DJ, van Gennip AH. Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G→A mutation causing DPD deficiency. Clin Cancer Res. 2001;7:1149–53. [PubMed]
57. Yamaguchi K, Arai Y, Kanda Y, Akagi K. Germline mutation of dihydropyrimidine dehydrogenese gene among a Japanese population in relation to toxicity to 5-Fluorouracil. Jpn J Cancer Res. 2001;92:337–42. [PubMed]
58. Hamdy SI, Hiratsuka M, Narahara K, El-Enany M, Moursi N, Ahmed MS, Mizugaki M. Allele and genotype frequencies of polymorphic cytochromes P450 (CYP2C9, CYP2C19, CYP2E1) and dihydropyrimidine dehydrogenase (DPYD) in the Egyptian population. Br J Clin Pharmacol. 2002;53:596–603. [PMC free article] [PubMed]
59. van Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, van Lenthe H, De Abreu RA, Maring JG, Vreken P, van Gennip AH. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res. 2000;6:4705–12. [PubMed]
60. Collie-Duguid ES, Etienne MC, Milano G, McLeod HL. Known variant DPYD alleles do not explain DPD deficiency in cancer patients. Pharmacogenetics. 2000;10:217–23. [PubMed]
61. Hsiao HH, Yang MY, Chang JG, Liu YC, Liu TC, Chang CS, Chen TP, Lin SF. Dihydropyrimidine dehydrogenase pharmacogenetics in the Taiwanese population. Cancer Chemother Pharmacol. 2004;53:445–51. [PubMed]
62. Crewe HK, Ellis SW, Lennard MS, Tucker GT. Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem Pharmacol. 1997;53:171–8. [PubMed]
63. Lee KH, Ward BA, Desta Z, Flockhart DA, Jones DR. Quantification of tamoxifen and three metabolites in plasma by high-performance liquid chromatography with fluorescence detection: application to a clinical trial. J Chromatogr B Anal Technol Biomed Life Sci. 2003;791:245–53. [PubMed]
64. Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, Flockhart DA. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2003;95:1758–64. [PubMed]
65. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97:2005. [PubMed]
66. Nowell SA, Ahn J, Rae JM, Scheys JO, Trovato A, Sweeney C, MacLeod SL, Kadlubar FF, Ambrosone CB. Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat. 2005;91:249–58. [PubMed]
67. Wegman P, Vainikka L, Stal O, Nordenskjold B, Skoog L, Rutqvist LE, Wingren S. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res. 2005;7:284–90. [PMC free article] [PubMed]
68. Lennard MS. Genetic polymorphism of sparteine/debrisoquine oxidation: a reappraisal. Pharmacol Toxicol. 1990;67:273–83. [PubMed]
69. Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics. 2002;3:229–43. [PubMed]
70. Gaedigk A, Gotschall RR, Forbes NS, Simon SD, Kearns GL, Leeder JS. Optimization of cytochrome P4502D6 (CYP2D6) phenotype assignment using a genotyping algorithm based on allele frequency data. Pharmacogenetics. 1999;9:669–82. [PubMed]
71. Sachse C, Brockmoller J, Bauer S, Roots I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet. 1997;60:284–95. [PMC free article] [PubMed]
72. Kirchheiner J, Heesch C, Bauer S, Meisel C, Seringer A, Goldammer M, Tzvetkov M, Meineke I, Roots I, Brockmoller J. Impact of the ultrarapid metabolizer genotype of cytochrome P450 2D6 on metoprolol pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2004;76:302–12. [PubMed]
73. Wang SL, Huang JD, Lai MD, Liu BH, Lai ML. Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects: polymorphism in RFLP and DNA sequence of CYP2D6. Clin Pharmacol Ther. 1993;53:410–8. [PubMed]
74. Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol. 1994;46:452–9. [PubMed]
75. Gaedigk A, Bradford LD, Marcucci KA, Leeder JS. Unique CYP2D6 activity distribution and genotype—phenotype discordance in black Americans. Clin Pharmacol Ther. 2002;72:76–89. [PubMed]
76. Ackland SP, Schilsky RL. High-dose methotrexate: a critical reappraisal. J Clin Oncol. 1987;5:2017–31. [PubMed]
77. Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE. Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci. 2001;22:195–201. [PubMed]
78. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR Studies Collaboration Group. MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002;288:2023–31. [PubMed]
79. Christensen B, Arbour L, Tran P, Leclerc D, Sabbaghian N, Platt R, Gilfix BM, Rosenblatt DS, Gravel RA, Forbes P, Rozen R. Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Am J Med Genet. 1999;84:151–7. [PubMed]
80. Cronin S, Furie KL, Kelly PJ. Dose-related association of MTHFR 677T allele with risk of ischemic stroke: evidence from a cumulative meta-analysis. Stroke. 2005;36:1581–7. [PubMed]
81. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111–3. [PubMed]
82. van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62:1044–51. [PMC free article] [PubMed]
83. Schneider JA, Rees DC, Liu YT, Clegg JB. Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet. 1998;62:1258–60. [PMC free article] [PubMed]
84. Wilcken B, Bamforth F, Li Z, Zhu H, Ritvanen A, Renlund M, Stoll C, Alembik Y, Dott B, Czeizel AE, Gelman-Kohan Z, Scarano G, Bianca S, Ettore G, Tenconi R, Bellato S, Scala I, Mutchinick OM, Lopez MA, de Walle H, Hofstra R, Joutchenko L, Kavteladze L, Bermejo E, Martinez-Frias ML, Gallagher M, Erickson JD, Vollset SE, Mastroiacovo P, Andria G, Botto LD. Geographical and ethnic variation of the 677C→T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet. 2003;40:619–25. [PMC free article] [PubMed]
85. van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, Mariman EC, den Heyer M, Rozen R, Blom HJ. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet. 1995;346:1070–1. [PubMed]
86. Toffoli G, Russo A, Innocenti F, Corona G, Tumolo S, Sartor F, Mini E, Boiocchi M. Effect of methylenetetrahydrofolate reductase 677C→T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients. Int J Cancer. 2003;103:294–9. [PubMed]
87. Toffoli G, Veronesi A, Boiocchi M, Crivellari D. MTHFR gene polymorphism and severe toxicity during adjuvant treatment of early breast cancer with cyclophosphamide, methotrexate, and fluorouracil (CMF) Ann Oncol. 2000;11:373–4. [PubMed]
88. Ulrich CM, Yasui Y, Storb R, Schubert MM, Wagner JL, Bigler J, Ariail KS, Keener CL, Li S, Liu H, Farin FM, Potter JD. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood. 2001;98:231–4. [PubMed]
89. Robien K, Schubert MM, Bruemmer B, Lloid ME, Potter JD, Ulrich CM. Predictors of oral mucositis in patients receiving hematopoietic cell transplants for chronic myelogenous leukemia. J Clin Oncol. 2004;22:1268–75. [PubMed]
90. Rustum YM, Harstrick A, Cao S, Vanhoefer U, Yin MB, Wilke H, Seeber S. Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors. J Clin Oncol. 1997;15:389–400. [PubMed]
91. Nishimura R, Nagaom K, Miyayama H, Matsuda M, Baba K, Matsuoka Y, Yamashita H, Fukuda M, Higuchi A, Satoh A, Mizumoto T, Hamamoto R. Thymidylate synthase levels as a therapeutic and prognostic predictor in breast cancer. Anticancer Res. 1999;19:5621–6. [PubMed]
92. Leichman CG, Lenz HJ, Leichman L, Danenberg K, Baranda J, Groshen S, Boswell W, Metzger R, Tan M, Danenberg PV. Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J Clin Oncol. 1997;15:3223–9. [PubMed]
93. van Triest B, Pinedo HM, van Hensbergen Y, Smid K, Telleman F, Schoenmakers PS, van der Wilt CL, van Laar JA, Noordhuis P, Jansen G, Peters GJ. Thymidylate synthase level as the main predictive parameter for sensitivity to 5-fluorouracil, but not for folate-based thymidylate synthase inhibitors, in 13 nonselected colon cancer cell lines. Clin Cancer Res. 1999;5:643–54. [PubMed]
94. Kornmann M, Link KH, Lenz HJ, Pillasch J, Metzger R, Butzer U, Leder GH, Weindel M, Safi F, Danenberg KD, Beger HG, Danenberg PV. Thymidylate synthase is a predictor for response and resistance in hepatic artery infusion chemotherapy. Cancer Lett. 1997;118:29–35. [PubMed]
95. Kaneda S, Nalbantoglu J, Takeishi K, Shimizu K, Gotoh O, Seno T, Ayusawa D. Structural and functional analysis of the human thymidylate synthase gene. J Biol Chem. 1990;265:20277–84. [PubMed]
96. Takeishi K, Kaneda S, Ayusawa D, Shimizu K, Gotoh O, Seno T. Human thymidylate synthase gene: isolation of phage clones which cover a functionally active gene and structural analysis of the region upstream from the translation initiation codon. J Biochem (Tokyo) 1989;106:575–83. [PubMed]
97. Kawakami K, Salonga D, Park JM, Danenberg KD, Uetake H, Brabender J, Omura K, Watanabe G, Danenberg PV. Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res. 2001;7:4096–101. [PubMed]
98. Horie N, Aiba H, Oguro K, Hojo H, Takeishi K. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct. 1995;20:191–7. [PubMed]
99. Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A, Warren R, Tsao-Wei D, Groshen S, Lenz HJ. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 2001;1:65–70. [PubMed]
100. Lecomte T, Ferraz JM, Zinzindohoue F, Loriot MA, Tregouet DA, Landi B, Berger A, Cugnenc PH, Jian R, Beaune P, Laurent-Puig P. Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy. Clin Cancer Res. 2004;10:5880–8. [PubMed]
101. Marsh S, McKay JA, Cassidy J, McLeod HL. Polymorphism in the thymidylate synthase promoter enhancer region in colorectal cancer. Int J Oncol. 2001;19:383–6. [PubMed]
102. Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ, Ladner RD. A novel single nucleotide polymorphism within the 5′-tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res. 2003;63:2898–904. [PubMed]
103. Kawakami K, Watanabe G. Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res. 2003;63:6004–7. [PubMed]
104. Marcuello E, Altes A, del Rio E, Cesar A, Menoyo A, Baiget M. Single nucleotide polymorphism in the 5′-tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int J Cancer. 2004;112:733–7. [PubMed]
105. Marsh S, McLeod HL. Thymidylate synthase pharmacogenetics in colorectal cancer. Clin Colorectal Cancer. 2001;1:175–8. [PubMed]
106. Villafranca E, Okruzhnov Y, Dominguez MA, Garcia-Foncillas J, Azinovic I, Martinez E, Illarramendi JJ, Arias F, Martinez Monge R, Salgado E, Angeletti S, Brugarolas A. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol. 2001;19:1779–86. [PubMed]
107. Iacopetta B, Grieu F, Joseph D, Elsaleh H. A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil. Br J Cancer. 2001;85:827–30. [PMC free article] [PubMed]
108. Krajinovic M, Costea I, Chiasson S. Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukaemia. Lancet. 2002;359:1033–4. [PubMed]
109. Wang TL, Diaz LAJ, Romans K, Bardelli A, Saha S, Galizia G, Choti M, Donehower R, Parmigiani G, Shih Ie M, Iacobuzio-Donahue C, Kinzler K, Vogelstein B, Lengauer C, Velculescu VE. Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proc Natl Acad Sci USA. 2004;101:3089–94. [PMC free article] [PubMed]
110. Mandola MV, Stoehlmacher J, Zhang W, Groshen S, Yu MC, Iqbal S, Lenz HJ, Ladner RD. A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics. 2004;14:319–27. [PubMed]
111. Kawakami K, Ishida Y, Danenberg KD, Omura K, Watanabe G, Danenberg PV. Functional polymorphism of the thymidylate synthase gene in colorectal cancer accompanied by frequent loss of heterozygosity. Jpn J Cancer Res. 2002;93:1221–9. [PubMed]
112. Uchida K, Hayashi K, Kawakami K, Schneider S, Yochim JM, Kuramochi H, Takasaki K, Danenberg KD, Danenberg PV. Loss of heterozygosity at the thymidylate synthase (TS) locus on chromosome 18 affects tumor response and survival in individuals heterozygous for a 28-bp polymorphism in the TS gene. Clin Cancer Res. 2004;10:433–9. [PubMed]
113. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol. 2002;20:1S–13S. [PubMed]
114. Perez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, Rigas J, Clark GM, Santabarbara P, Bonomi P. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol. 2004;22:3238–47. [PubMed]
115. Shepherd F, Pereira J, Ciuleanu T, Tan E, Hirsh V, Thongprasert S, Bezjak A, Tu D, Santabarbara P, Seymour L. A randomized placebo controlled study of erlotinib (OSI-774, TarcevaTM) versus placebo in patients with incurable non-small-cell lung cancer who have failed standard therapy for advanced or metastatic disease. Proc Am Soc Clin Oncol. 2004;22:7022.
116. Thatcher N, Chang A, Parikh P, Pemberton K, Archer V. Results of a Phase III placebo-controlled study (ISEL) of gefitinib (IRESSA) plus best supportive care (BSC) in patients with advanced non-small-cell lung cancer (NSCLC) who had received 1 or 2 prior chemotherapy regimens. Proc Am Assoc Cancer Res. 2005;46:LB6.
117. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong RP, Baselga J. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected] J Clin Oncol. 2003;21:2237–46. [PubMed]
118. Parra HS, Cavina R, Latteri F, Zucali PA, Campagnoli E, Morenghi E, Grimaldi GC, Roncalli M, Santoro A. Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib (‘Iressa’, ZD1839) in non-small-cell lung cancer. Br J Cancer. 2004;91:208–12. [PMC free article] [PubMed]
119. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39. [PubMed]
120. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500. [PubMed]
121. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H. EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004;101:13306–11. [PMC free article] [PubMed]
122. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–92. [PubMed]
123. Mitsudomi T, Kosaka T, Endoh H, Horio Y, Hida T, Mori S, Hatooka S, Shinoda M, Takahashi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol. 2005;23:2513–20. [PubMed]
124. Han SW, Kim TY, Hwang PG, Jeong S, Kim J, Choi IS, Oh DY, Kim JH, Kim DW, Chung DH, Im SA, Kim YT, Lee JS, Heo DS, Bang YJ, Kim NK. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2005;23:2493–501. [PubMed]
125. Takano T, Ohe Y, Sakamoto H, Tsuta K, Matsuno Y, Tateishi U, Yamamoto S, Nokihara H, Yamamoto N, Sekine I, Kunitoh H, Shibata T, Sakiyama T, Yoshida T, Tamura T. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol. 2005;23:6829–37. [PubMed]
126. Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli G, Bemis L, Haney J, Witta S, Danenberg K, Domenichini I, Ludovini V, Magrini E, Gregorc V, Doglioni C, Sidoni A, Tonato M, Franklin WA, Crino L, Bunn PAJ, Varella-Garcia M. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005;97:643–55. [PubMed]
127. Perez-Soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol. 2005;23:5235–46. [PubMed]
128. Liu W, Innocenti F, Wu MH, Desai AA, Dolan ME, Cook EHJ, Ratain MJ. A functional common polymorphism in a Sp1 recognition site of the epidermal growth factor receptor gene promoter. Cancer Res. 2005;65:46–53. [PubMed]
129. Gebhardt F, Zanker KS, Brandt B. Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J Biol Chem. 1999;274:13176–80. [PubMed]
130. Amador ML, Oppenheimer D, Perea S, Maitra A, Cusati G, Iacobuzio-Donahue C, Baker SD, Ashfaq R, Takimoto C, Forastiere A, Hidalgo M. An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors. Cancer Res. 2004;64:9139–43. [PubMed]
131. Sachidanandam R, Weissman D, Schmidt SC, Kakol JM, Stein LD, Marth G, Sherry S, Mullikin JC, Mortimore BJ, Willey DL, Hunt SE, Cole CG, Coggill PC, Rice CM, Ning Z, Rogers J, Bentley DR, Kwok PY, Mardis ER, Yeh RT, Schultz B, Cook L, Davenport R, Dante M, Fulton L, Hillier L, Waterston RH, McPherson JD, Gilman B, Schaffner S, van Etten WJ, Reich D, Higgins J, Daly MJ, Blumenstiel B, Baldwin J, Stange-Thomann N, Zody MC, Linton L, Lander ES, Altshuler D. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature. 2001;409:928–33. [PubMed]
132. Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I. Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos. 2005;33:434–9. [PubMed]
133. Innocenti F, Undevia SD, Rosner GL, Xiao L, Liu W, Chen P, Das S, Ramirez J, Kroetz DL, Ratain MJ. Irinotecan (CPT-11) pharmacokinetics (PK) and neutropenia: interaction among UGT1A1 and transporter genes. Proc Am Soc Clin Oncol. 2005;23:2006.

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...