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Clinical Cancer Research Vol. 12, 854-859, February 2006
© 2006 American Association for Cancer Research

Cancer Therapy: Clinical

mdr-1 Single Nucleotide Polymorphisms in Ovarian Cancer Tissue: G2677T/A Correlates with Response to Paclitaxel Chemotherapy

Henrik Gréen1, Peter Söderkvist2, Per Rosenberg3, György Horvath4 and Curt Peterson1

Authors' Affiliations: 1 Division of Clinical Pharmacology, Department of Medicine and Care; 2 Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University; 3 Department of Oncology, Linköping University Hospital, Linköping; and 4 Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden

Requests for reprints: Henrik Gréen, Division of Clinical Pharmacology, Department of Medicine and Care, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden. Phone: 46-13-221229; Fax: 46-13-104195; E-mail: henrik.green{at}imv.liu.se.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: P-glycoprotein, encoded by the mdr-1 gene, confers multidrug resistance to a variety of antineoplastic agents, e.g., paclitaxel. Recently, different polymorphisms in the mdr-1 gene have been identified and their consequences for the function of P-glycoprotein, as well as for the treatment response to P-glycoprotein substrates, are being clarified. We analyzed the allelic frequencies at polymorphic sites G2677T/A and C3435T in ovarian cancer patients with good or poor response to treatment with paclitaxel in combination with carboplatin in order to evaluate their predictive values.

Experimental Design: Fifty-three patients were included in the study; 28 of them had been relapse-free for at least 1 year and 25 had progressive disease or relapsed within 12 months. A reference material consisting of 200 individuals was also analyzed. The genotypes of each single nucleotide polymorphism (SNP) were determined using Pyrosequencing.

Results: The G2677T/A SNP was found to significantly correlate with treatment outcome. The probability of responding to paclitaxel treatment was higher in homozygously mutated patients (T/T or T/A; Fisher's exact test; P < 0.05). The frequency of the T or A alleles was also higher in the group of patients who had a good response (P < 0.05). There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment ({chi}2 test for linear-by-linear association; P = 0.03). However, the C3435T SNP was not found to correlate to treatment outcome.

Conclusions: The mdr-1 polymorphism G2677T/A in exon 21 correlates with the paclitaxel response in ovarian cancer and may be important for the function of P-glycoprotein and resistance to paclitaxel and provide useful information for individualized therapy.

Paclitaxel (Taxol) has a broad spectrum of activity and is clinically used to treat breast, ovarian, and lung cancer (1). Paclitaxel was originally isolated from the stem bark of the Pacific yew tree, Taxus brevifolia (2). Drug resistance is a major obstacle to the successful treatment of cancer patients and several potential mechanisms have been reported to account for resistance to paclitaxel. These include decreased sensitivity to apoptosis-inducing stimuli (3), alterations in tubulin binding and microtubule dynamics (4), and overexpression of the transport protein P-glycoprotein (5). P-glycoprotein, encoded by the mdr-1 gene, is a 170 kDa plasma membrane protein that functions as an ATP-driven drug export pump. The taxanes and other cytotoxic drugs of natural origin can be extruded by P-glycoprotein through the cell membranes and enhanced expression on tumor cells leads to a resistant phenotype (6, 7). A high expression of P-glycoprotein on tumor cells has been shown to correlate with a poor response to paclitaxel treatment (8, 9).

P-glycoprotein is also expressed in nonmalignant tissues, e.g., in the intestine and the blood-brain barrier, and influences the activity and distribution of different drugs. In the intestine, P-glycoprotein has proved to be a major determinant for the intestinal absorption of such drugs as protease inhibitors, ß-blockers, cyclosporine A, and digoxin (10). At the blood-brain barrier, P-glycoprotein is important for the distribution of various substances to the central nervous system and therefore may be of importance not only for the therapeutic effect of psychopharmacologic drugs, but also for the central neurotoxicity of chemotherapeutic agents and pesticides (11).

The first report on the polymorphisms of the mdr-1 gene was presented in the late 1980s, and the sequence variant showed an altered resistance phenotype (12). However, it was not until 2000 when Hoffmeyer et al. systematically screened the mdr-1 gene for sequence variations that the functional importance of these polymorphisms was shown. They indicated that the synonymous single nucleotide polymorphism (SNP) in exon 26, C3435T, correlated with the level of expression of P-glycoprotein in the intestine. Individuals homozygous for this SNP had lower P-glycoprotein expression and showed higher plasma levels of the P-glycoprotein substrate digoxin (13). Up to now, more than 25 SNPs have been reported for the mdr-1 gene, resulting in up to 20 coding region variants (14–16). However, most SNPs are present at very low frequencies and there are large interethnic variations (14). In Caucasians, the SNPs G2677T/A and C3435T have been considered most interesting because they have been shown to correlate with the P-glycoprotein expression and phenotype (13, 17).

A nonfunctional P-glycoprotein could affect the pharmacokinetics and pharmacodynamics of paclitaxel in several ways. Cancer cells with an ineffective P-glycoprotein efflux should be more sensitive to the drug. Secondly, paclitaxel is given i.v. and excreted via the feces, hence, ineffective transport of paclitaxel from the blood circulation to the intestine would increase the systemic exposure of the drug. We therefore designed this study to evaluate the effect of the mdr-1 sequence variants G2677T/A and C3435T on the response to paclitaxel treatment in ovarian cancer.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
The allele frequencies of the mdr-1 SNPs G2677T/A and C3435T were investigated in a Swedish population. DNA samples (n = 200) were taken from a regional DNA bank consisting of genomic DNA isolated from randomly selected individuals in the southeastern part of Sweden after obtaining their informed consent.

To evaluate the relationship between the mdr-1 genotype and the response to paclitaxel treatment, we identified the SNPs in 51 epithelial ovarian tumors and two fallopian tube carcinomas from two groups of patients. After primary surgery, all patients had been treated with paclitaxel at a dose of 175 or 135 mg/m2 (n = 5) in combination with carboplatin for at least four cycles. The patients were treated according to the same treatment protocol at Linköping University Hospital or Sahlgrenska University Hospital, Gothenburg, in the southern part of Sweden. In the first group, the patients had a complete response and were relapse-free for at least 1 year (defined as a good response). In the other group, the patients had progressive disease during treatment or had a relapse within 12 months (defined as a poor response). The patient and tumor characteristics are presented in Table 1.


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  		Table 1. Patient and tumor characteristics

 
Eleven tumors were collected from paraffin-embedded tissues stored at the Division of Molecular and Immunological Pathology, Linköping University, and 42 tumors were fresh-frozen and obtained from a bio-bank at the Department of Oncology, Sahlgrenska University Hospital, Gothenburg. The local ethics committee approved the study.

DNA isolation and PCR. After tumor collection, genomic DNA was isolated using QIAamp DNA mini kits (VWR International, Stockholm, Sweden) according to the manufacturer's protocol. The amount of DNA extracted was quantified by absorbance spectroscopy (260 and 280 nm) and diluted to 10 ng/µL for working solutions. The isolated DNA was stored at –70°C and the working solutions were stored at –20°C.

The sequence of the PCR primers (Table 2) for amplifications of exon 21 and exon 26 was designed using primer 0.5 free software and checked for specificity using the National Center for Biotechnology Information BLAST server (http://www.ncbi.nlm.nih.gov/blast/). One primer for each PCR product was biotinylated in its 5'-end for purification of ssDNA. All primers were obtained from Invitrogen (Paisley, United Kingdom).


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  		Table 2. PCR primers, sequencing primers and dispensation order for detecting the mdr-1 SNPs

 
The PCR reactions were based on the HotStarTaq master mixture (VWR International) and carried out on a Mastercycler gradient (Eppendorf, Hamburg, Germany) in a total volume of 25 µL. The reactions were optimized for annealing temperature (58°C) and MgCl2 concentration (1.5 mmol/L). Each PCR primer was used at a concentration of 0.4 µmol/L and each reaction used 25 ng of human genomic DNA as template. The amplification was done with the following temperature cycles: 1 cycle at 95°C for 15 minutes; 50 cycles at 95°C for 30 seconds, at 58°C for 30 seconds, and at 72°C for 30 seconds; followed by 1 cycle at 72°C for 10 minutes.

All PCR products were sequenced using both forward and reverse primers on a MegaBACE 1000 (Amersham Biosciences, Uppsala, Sweden) and the sequences were consistent with mdr-1 gene in the GenBank sequence AC005068.

Pyrosequencing. For the real-time sequencing of the PCR products and SNP analysis, Pyrosequencing PSQ96MA (Pyrosequencing AB, Uppsala, Sweden) was used. Sequence-specific primers (Table 2) were designed with the software provided by Pyrosequencing AB (http://www.pyrosequencing.com). Pyrosequencing was done according to the manufacturer's protocol. In brief, for each genotype, ssDNA was isolated from the PCR reactions using the Pyrosequencing Vacuum Prep Workstation (Pyrosequencing AB). Streptavidin Sepharose high performance beads (Amersham Biosciences) were dissolved in BW buffer (10 mmol/L Tris-HCl, 2 mol/L NaCl, 1 mmol/L EDTA, 1 mL/L Tween, pH 7.6; Sigma, Stockholm, Sweden) and added to the PCR reactions and mixed (>1,300 rpm) for 5 minutes at room temperature. The beads with the captured DNA were washed in ethanol (70%, Kemetyl, Stockholm, Sweden), transferred to 0.2 mol/L NaOH (Sigma) and flushed with washing buffer (10 mmol/L Tris-acetate, 5 mmol/L magnesium acetate, pH 7.6; Sigma). The beads were then released into a 96-well plate containing annealing buffer (10 mmol/L Tris-acetate, 5 mmol/L magnesium acetate, pH 7.6; Sigma) and, for each genotype, the specific sequencing primer (Table 2). Annealing was done by heating the sample at 80°C for 2 minutes and then allowing it to cool to room temperature. The plate was then transferred to the PSQ96MA where the real-time sequencing took place. The dispensation order for each genotype is presented in Table 2.

Statistical analysis. The statistical analysis was done with the SPSS software package version 11.5.1 (SPSS, Inc. Chicago, IL). The significance of differences in allele frequencies and genotypes between good and poor responders was calculated using generalized Fisher's exact test (the P values for the two-sided exact significance are presented). For differences in which P < 0.05, the relative risk of responding to treatment with a 95% confidence interval was calculated when applicable. The {chi}2 test for linear-by-linear association was used to analyze the significance of trends in different tables (the P values for the two-sided exact significance are presented). For these calculations, the wild-type genotypes were denoted as 0, the heterozygous as 1, and the homozygous as 2.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
The PCR amplification of exon 21 and exon 26 of the mdr-1 gene resulted in single products of expected sizes (as judged by agarose gel electrophoresis) and the sequences of the products were consistent with that of the mdr-1 gene. The pyrograms during real-time sequencing showed peaks corresponding to each genotype as shown in Figs. 1 and 2. All allele combinations, except the homozygous A/A at position 2677, were found in the individuals studied.


Figure 1
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  		Fig. 1. Representative pyrograms for genotyping the C3435T SNP, illustrating (A) an individual homozygous wild-type (C/C), (B) a heterozygous (C/T), and (C) a T homozygous individual (T/T). The sequencing was done on the forward strand.

 

Figure 2
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  		Fig. 2. Representative pyrograms for the genotyping of the G2677T/A SNP illustrating (A) a homozygous wild-type (G/G), (B) a heterozygous G/T, (C) a T homozygous individual (T/T), (D) a G/A heterozygous individual, and (E) a T/A heterozygous. No homozygous A/A was found in the individuals studied. The sequencing was done on the reverse strand.

 
The frequencies of G2677T/A and C3435T were investigated in individual DNA samples from the reference population (Table 3). The frequencies of the altered sequences were high at both locations. We also found a correlation between the two SNPs, indicating that they are linked to the same haplotype in certain individuals (Table 4; P < 0.001). In the patients with ovarian cancer, the frequencies of C3435T and G2677T/A were comparable with the percentages found in the reference population (Table 3). There was no significant difference in patient and tumor characteristics between good and poor responders.


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  		Table 3. The SNP frequencies in a Swedish population (n = 200) and in patients with ovarian cancer

 

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  		Table 4. mdr-1 genotypes in a general Swedish population and in ovarian cancer patients that had been successfully treated with paclitaxel and those that failed treatment

 
The distributions of the mdr-1 SNPs in good and poor responders are shown in Table 4. The missense SNP, G2677T/A, correlated with the outcome of paclitaxel treatment. We compared the wild-type and heterozygous (G/G and G/T) with the homozygously mutated (T/T and T/A) patients and their relation to treatment outcome (Fig. 3A). A statistically significant correlation was found between homozygously mutated patients and successful treatment with paclitaxel (P < 0.05, Fisher's exact test). Nine of the 28 cases with a good response were homozygously mutated compared with 2 of the 25 cases with a poor response. The frequency of the T and A alleles in the group of patients with a good response was also significantly higher than in poor responders (32 of 56 compared with 18 of 50; P < 0.05, Fisher's exact test) as shown in Fig. 3B. The effect of increasing number of mutated alleles (G/G < G/T < T/T or T/A) on the treatment outcome was also found to be significant ({chi}2 test for linear-by-linear association; P = 0.03; Fig. 3C). This shows that homozygously mutated patients are more likely to respond to treatment than heterozygous ones, who in turn have a better prognosis than individuals carrying the G/G genotype. The allelic variants of the C3435T SNP did not, however, correlate with the outcome of paclitaxel treatment in patients with ovarian cancer.


Figure 3
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  		Fig. 3. The effect of the mdr-1 SNP G2677T/A on the treatment outcome. A, the treatment outcome, good response (white) and poor response (black), was evaluated for homozygously mutated individuals (T/T or T/A) and compared with the response of the individuals having G/G or G/T at position 2677. Patients who were homozygously mutated were significantly more likely to respond to paclitaxel treatment than patients carrying the other genotypes (Fisher's exact test, P = 0.04; relative risk, 1.81; 95% confidence interval for the relative risk: 1.17 < relative risk < 2.79). B, the nucleotide frequencies (2 x homozygous + heterozygous) in the two treatment groups were also compared using an exact test. A significantly higher frequency of T or A at position 2677 was found in the group of patients that had responded well to treatment compared with those who responded poorly (Fisher's exact test, P = 0.03; relative risk, 1.59; 95% confidence interval for the relative risk: 1.03 < relative risk < 2.45). C, the dose response effect of the allele variants on the success and failure of paclitaxel treatment was tested using the {chi}2 test for linear-by-linear association and was found to be significant ({chi}2 test for linear-by-linear association, P = 0.03).

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Patients with ovarian cancer who are homozygously mutated for the G2677T/A mdr-1 SNP are more likely to respond to paclitaxel treatment and the presence of two mutated alleles can be considered a predictive factor for successful treatment. One explanation could be that the G2677T/A polymorphism has a functional consequence on P-glycoprotein-mediated paclitaxel transport. The better response might be due to a reduced efflux of paclitaxel from the tumor cells or a reduced elimination from the body, giving higher plasma concentrations. However, in our study, there was no indication of increased adverse drug reactions in patients with mutations. The C3435T variant did not affect treatment outcome.

There are several confounders, which could contribute to the results. A larger number of tumors with a low Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage were actually selected in the group of good responders (Table 1). However, when excluding patients with FIGO stage I or II from the material, the correlations presented here still maintain the same level of significance (P < 0.05). To ensure that the total drug dose did not affect the correlation, we only included patients who received at least four cycles of paclitaxel treatment and the mean number of cycles in the two groups was similar (good response, mean = 7.1 cycles, and poor response, mean = 7.8 cycles). Five patients received a lower dose of paclitaxel (135 mg/m2). Two of these patients were poor responders and three were good responders. A larger number of patients in the group with a good response had no macroscopic tumor remaining after surgery or the result of surgery was not known. Five of these 11 patients had a late relapse, indicating that they still had some tumor residues after surgery. As for the other six patients, we cannot be sure whether the treatment outcome is due to the chemotherapy or to the surgery. However, excluding these patients from the material, the correlation between the response and the G2677T/A SNPs is still significant (P < 0.05).

Several drug resistance–associated genes have been described and characterized in cell lines but their precise roles in clinical resistance still remain to be clarified. This is also true for the extensively studied mdr-1 gene and its product P-glycoprotein. Although P-glycoprotein, MRP1, MRP2, MRP3, MRP6, and MRP7 are able to confer resistance to natural products in cell lines, P-glycoprotein and MRP-7 are the only two that cause an efflux of paclitaxel (18, 19). In the treatment of ovarian cancer with paclitaxel, it has been shown that P-glycoprotein expression in tumors correlates with a poor response (8, 9).

Several groups have investigated the effects of the mdr-1 polymorphisms on the development of drug resistance and relapse after chemotherapy as well as on the pharmacokinetics of antineoplastic agents. Illmer et al. found that acute myeloid leukemia patients with the wild-type variant of C1236T, G2677T/A, and C3435T had a higher risk of relapse than the other haplotypes (20). Our results support these findings because ovarian cancer patients with the wild-type variant and the heterozygous patients did not respond to paclitaxel treatment as well as individuals homozygously mutated at position 2677. Several other groups have found that the wild-type of the silent C3435T variant is associated with poor response (20–22). Although we could not detect an effect of the C3435T SNP on the outcome, we and others have shown that there is a linkage between the two SNPs (15, 16, 23). It has been proposed that the effect observed when studying one of the SNPs might be due to the other one (23). Considering this linkage, the effect on treatment outcome in ovarian cancer is also supported by the findings of Jamroziak et al. showing that children with acute lymphoblastic leukemia and the C/C genotype at position 3435 have a worse prognosis (21). When treating breast cancer patients with anthracyclines alone or in combination with taxanes, Kafka et al. found that the T/T variant at position 3435 correlated with a complete clinical response (22). All of these studies including ours indicate that patients having one or more wild-type alleles of the SNPs are at higher risk of not responding to treatment. On the other hand, Isla et al. did not find any effect of the C3435T mdr-1 polymorphism on the outcome of docetaxel-cisplatin treatment of patients with non–small cell lung cancer (24). In contrast with our results, the haplotype of 2677T/T and 3435T/T has also been shown to be at highest risk of drug resistance in lymphoproliferative diseases (25). Because most studies have been done on the silent mutation, C3435T, the discrepancies in the results might be due to the association of this SNP with different haplotypes in different populations. The contradictions might also be explained by the consideration that the different amino acids at position 893 (Ala, Ser, or Thr, nucleotide position 2677) might have different effects on different drugs.

The functional consequences of the mdr-1 SNPs have not been extensively studied in vitro. Kimchi-Sarfaty et al. showed that the efflux of paclitaxel in vitro by the wild-type P-glycoprotein was slightly higher then the efflux seen with cells carrying a plasmid containing the 2677T variant (26). In contrast, for other substrates such as verapamil, vinblastine, calcein-AM, prazosin, bisantrene, forskolin, digoxin (0.1 µmol/L), and cyclosporin A the transport was not affected by known variants of P-glycoprotein, however, for each substrate, only one concentration was tested (23, 26, 27). Unexpectedly an enhanced efflux has been reported for digoxin in a very high concentration (50 µmol/L) in cells expressing the mdr-1 Ser893 variant (2677T), indicating differences in substrate specificity for the different variants of P-glycoprotein (28).

The functionality of P-glycoprotein might not only affect the response of the tumor cells but might affect drug disposition as well. Sparreboom et al. showed that mdr1a(–/–) mice (lacking intestinal P-glycoprotein) have much higher plasma concentrations of paclitaxel and lower excretion via the bile compared with wild-type mice, establishing an important role for P-glycoprotein in the transport of paclitaxel from the circulation to the intestinal lumen (29). In humans, this is supported by findings showing that concomitant administration of P-glycoprotein blockers and paclitaxel decreases the paclitaxel clearance and increases the exposure of paclitaxel (area under the curve; ref. 30). The effect of the mdr-1 polymorphism on paclitaxel pharmacokinetics has not yet been shown. In other studies, no significant differences in the clearance of docetaxel were observed between different mdr-1 genotypes (31, 32), although the patients with C/C at position 3435 showed the highest docetaxel clearance (31). This suggests that fecal elimination is reduced by inhibiting P-glycoprotein-mediated transport in the gastrointestinal tract and that a nonfunctional P-glycoprotein may affect the pharmacokinetics of paclitaxel.

In conclusion, our study shows that patients with ovarian cancer who are homozygously mutated for the missense mdr-1 SNP, G2677T/A, respond better to treatment with paclitaxel than those with at least one wild-type allele. Obviously, further studies are needed before the role of the polymorphisms in the mdr-1 gene can be defined conclusively. Studies that show a correlation of SNP in the mdr-1 gene and the function or expression of P-glycoprotein contribute to the pool of information on the genetic background that may be relevant to predicting the individual response to treatment.


   Acknowledgments
 
We thank Isaac Austin for linguistic revision of the text and Olle Eriksson (Division of Statistics, Department of Mathematics, Linköping University) for his help with the statistics.


   Footnotes
 
Grant support: Swedish Cancer Society, Gunnar Nilsson's Cancer Foundation, and the County Council in Östergötland.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5/ 2/05; revised 10/18/05; accepted 11/ 8/05.


   References
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 Materials and Methods
 Results
 Discussion
 References
 

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