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Clinical Cancer Research Vol. 11, 3778-3783, May 15, 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Prognostic Role of Thymidylate Synthase Polymorphisms in Gastric Cancer Patients Treated with Surgery and Adjuvant Chemotherapy

Kazuyuki Kawakami1, Francesco Graziano2, Go Watanabe1, Annamaria Ruzzo3, Daniele Santini4, Vincenzo Catalano6, Renato Bisonni8, Federica Arduini9, Italo Bearzi9, Stefano Cascinu10, Pietro Muretto7, Giuseppe Perrone5, Carla Rabitti5, Lucio Giustini8, Giuseppe Tonini4, Francesca Pizzagalli3 and Mauro Magnani3

Authors' Affiliations: 1 Department of Surgery, Kanazawa University School of Medicine, Kanazawa, Japan; 2 Medical Oncology Unit, Hospital of Urbino; 3 Institute of Biochemistry "G Fornaini," University of Urbino, Urbino, Italy; 4 Medical Oncology Unit and 5 Institute of Pathology, University Campus Biomedico, Rome, Italy; 6 Medical Oncology Unit and 7 Department of Histopathology, Hospital of Pesaro, Pesaro Italy; 8 Medical Oncology Unit, Hospital of Fermo, Fermo, Italy; and 9 Institute of Pathology and 10 Medical Oncology Unit, University of Ancona, Ancona, Italy

Requests for reprints: Francesco Graziano, Medical Oncology Unit, Hospital of Urbino, via Bonconte da Montefeltro, 61029 Urbino, Italy. Phone: 39-722-301251; Fax: 39-722-301289; E-mail: frada{at}tin.it.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: To investigate the prognostic role of thymidylate synthase (TS) polymorphisms in gastric cancer patients treated with radical surgery and fluorouracil-based adjuvant chemotherapy.

Experimental Design: Ninety gastric cancer cases were identified among 187 patients previously enrolled in prospective case-control studies for disease susceptibility. Patients were genotyped for a G/C nucleotide change within a triple 28 bp variable number of tandem repeat sequence in the TS 5'-untranslated region (5'-UTR) and a 6 bp deletion in the TS 3'-untranslated region (3'-UTR). According to available functional data, patients with 5'-UTR 2R/2R, 2R/3C, 3C/3C genotypes were classified as low TS producers (5'-UTRlow) and patients with 5'-UTR 3G/3G, 3G/3C, 2R/3G genotypes as high TS producers (5'UTRhigh). Patients with 3'-UTR del6/del6 and del6/ins6 genotypes were classified as low TS producers (3'-UTRlow) and patients with 3'-UTR ins6/ins6 genotype as high TS producers (3'-UTRhigh). The prognostic analysis was based on 5'-UTR/3'-UTR combined genotypes.

Results: Ten patients (11%) were 5'-UTRhigh/3'-UTRhigh, 36 patients were 5'-UTRhigh/3'-UTRlow, 19 patients were 5'-UTRlow/3'-UTRhigh, and 25 patients were 5'-UTRlow/3'-UTRlow. 5'-UTRlow/3'-UTRlow patients showed the best outcome and the threshold of statistical significance was achieved in the comparison of disease-free survival and overall survival with 5'-UTRhigh/3'-UTRlow patients and 5'-UTRhigh/3'-UTRhigh patients. The presence of at least one high TS expression genotype showed independent adverse prognostic role in multivariate analysis.

Conclusions: The prognostic role of TS polymorphisms in gastric cancer deserves further investigation because the adverse effect of high TS expression genotypes may be a relevant information to improve adjuvant chemotherapeutic strategies.

Key Words: gastric neoplasms • thymidylate synthase • polymorphism • prognosis

Even after radical surgery, the prognosis of the majority of patients with gastric cancer remains unfavorable (1). Postoperative American Joint Committee on Cancer (AJCC) stage in patients with localized gastric carcinoma is often stage II or higher; for the R0 group, a median survival time of 35 months and a 5-year survival rate of up to 40% has been achieved in selected patients receiving postoperative adjuvant chemoradiation (1). Meta-analyses of adjuvant chemotherapy trials have confirmed a small survival benefit in favor of the systemic medical treatment, which is still fluorouracil based (2). The primary mechanism of action of fluorouracil is the inhibition of the DNA-synthetic enzyme thymidylate synthase (TS). For this to happen, the prodrug fluorouracil is converted to FdUMP, which form a covalently linked FdUMP–TS–5,10-methylenetetrahydrofolate ternary complex (3).

Single nucleotide polymorphisms and variable number of tandem repeats (VNTR) polymorphisms are common genetic variants that may occur in regulatory regions of the human genome and cause interindividual differences in the efficacy of molecular/metabolic pathways, like drug metabolism and drug sensitivity enzymes (3). Increasing evidence supports the role-specific polymorphisms in the TS gene for determining sensitivity to fluorouracil (4, 5). The first and extensively studied functional polymorphism in the TS promoter is a VNTR, which consists of either two or three 28 bp repeated sequence in the 5'-untranslated region (5'-UTR; ref. 6). The 3R allele has been related to enhanced TS expression when compared with the 2R allele and the greatest effect was observed in the presence of the homozygous 3R/3R genotype (7, 8). A G/C polymorphism within the 3R VNTR produces two additional alleles (3G or 3C) at this locus (9, 10). The 3G allele has been associated with increased transcriptional and mRNA translational activity in vitro (9, 10). In vivo, 3G-containing genotypes (2R/3G, 3C/3G, 3G/3G) have been found to correlate with high TS mRNA levels, which may induce chemoresistance to agents inhibiting the TS enzyme. Another TS polymorphism is a 6 bp deletion in the 3'-untranslated region (3'-UTR; ref. 11). Colorectal carcinomas with ins6/ins6 genotype showed a trend for higher TS mRNA levels than tumors with del6/del6 genotype (12). Recent findings seem to confirm that the TS 3'-UTRdel6 allele determines low TS mRNA stability and low TS expression in comparison with TS 3'-UTRins6 allele (13).

The need for more effective adjuvant treatment strategies in surgically resected, gastric cancer patients and the opportunity of a potential genetic screening for determining the efficacy of fluoropyrimidines prompted us to investigate the prognostic role of TS polymorphisms in patients with gastric cancer treated with fluorouracil-based adjuvant chemotherapy.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Between 1999 and 2002, 187 patients with gastric cancer were prospectively accrued in two case-control studies for disease susceptibility (14, 15). According to clinical practice in each participating institution, adjuvant chemotherapy was given to 90 high-risk patients (48%) who had undergone radical surgery (R0) with a minimum of D1 lymphadenectomy and a follow-up time of ≥3 years. Patients were treated with fluorouracil-based regimens, which showed activity in advanced disease: 5-fluorouracil/folinic acid as the so-called "de Gramont regimen" (16) in 20 patients, the same schedule of 5-fluorouracil/folinic acid plus mytomicin-C or cisplatin (17) in 45 patients, and a weekly schedule of 5-fluorouracil/folinic acid and cisplatin (18) in 25 patients. Follow-up procedures consisted of interim history, physical examination, hematologic studies, carcinoembryonic antigen levels, and diagnostic imaging (chest X-ray and abdominal ultrasonography) every 4 months in the first year and every 6 months thereafter. Patients underwent upper endoscopy 6 months after surgery and every 12 months thereafter. Whole-body computed tomography was done for corroborative evidence of relapse. The recurrences of gastric carcinoma had to be proven by cytology biopsy or surgery. The 1997 revision of the AJCC manual was used for the classification of each case. The study was done in a blind fashion so that patient outcome was unknown to investigators performing molecular analyses. The ethical committees approved the investigation and patients supplied a written informed consent.

Lymphocyte genomic DNA was extracted from peripheral blood samples of accrued patients. PCR and PCR-RFLP methods were used for analyzing the TS5'-UTR VNTR-G/C polymorphisms and the TS3'UTRdel6ins6 polymorphism as described previously (10, 15).

Statistical methods. According to previous studies (10, 12, 13), patients with TS5'-UTR 2R/2R, 2R/3C, 3C/3C genotypes were classified as low TS producers (TS5'-UTRlow), and patients with TS5'-UTR 3G/3G, 3G/3C, 2R/3G genotypes as high TS producers (TS5'-UTRhigh). Patients with TS3'-UTR del6/del6 or del6/ins6 genotypes were classified as low TS producers (TS3'-UTRlow) and patients with homozygous TS3'-UTR ins6ins6 genotype as high TS producers (TS3'-UTRhigh). Given the concomitant effect of TS 5'-UTR and TS 3'-UTR polymorphisms on TS expression and the linkage disequilibrium between the two loci (15, 19), the prognostic analysis was based on TS 5'-UTR/TS 3'-UTR combined genotypes.

Disease-free survival was measured from the date of surgery to the time of confirmed relapse. Overall survival was measured from the date of surgery to the time of death from any cause. The Kaplan-Meier method and the log-rank test were adopted to estimate and compare survival curves. The Cox proportional hazards model was used to assess the prognostic importance of genotypes adjusting for the following clinicopathologic features: age, gender, tumor size and location, grading, and AJCC tumor stage. Contingency tables were analyzed by the {chi}2 test. All of the values were two-sided and statistical significance was defined as P < 0.05.


   Results
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Discussion
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The distribution of clinical and primary tumor characteristics according to TS genotypes in the 90 patients are shown in Table 1. Clinicopathologic features did not show any correlation with TS genotypes (Table 1). At the time of the writing of this report, 54 patients (60%) had died with recurrent disease and 36 patients (40%) were disease free.


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  		Table 1. Characteristics of the 90 patients and their distribution according to TS genotypes

 
As shown in Table 2, the four patterns of TS combined genotypes were 5'-UTRlow/3'-UTRlow in 25 patients (28%), group A; 5'-UTRlow/3'-UTRhigh in 19 patients (21%), group B; 5'-UTRhigh/3'-UTRlow in 36 patients (40%), group C; and 5'-UTRhigh/3'-UTRhigh in 10 patients (11%), group D. The distribution of relapsed and disease-free patients between the four groups was significantly different (P = 0.003).


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  		Table 2. Distribution of relapsed and disease-free patients according to TS combined genotypes

 
Prognosis and thymidylate synthase combined genotypes. In the whole group, the 3-year disease-free survival rate was 54% and the 3-year overall survival rate was 68%. Three-year disease-free survival and overall survival rates in the four groups of TS combined genotypes are shown in Table 3. Carriers of both low TS expression genotypes (group A patients) showed the best outcome and the threshold of statistical significance was achieved in the comparison of their disease-free survival (Fig. 1A) and overall survival (Fig. 1B) with group C and group D patients (Table 3). The survival comparisons between carriers of only one high TS expression genotype (group B versus group C patients) did not show significant differences (Table 3). Group B and group C patients showed significantly better disease-free survival and overall survival than patients with both high TS expression genotypes in group D (Fig. 1; Table 3).


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  		Table 3. Three-year disease-free survival and overall survival rates in the four groups and results of the log-rank test

 


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  		Fig. 1. Disease-free survival (A) and overall survival (B) of gastric cancer patients in the four groups of TS combined genotypes: group A, 5'-UTRlow/3'-UTRlow; group B, 5'-UTRlow/3'-UTRhigh; group C, 5'-UTRhigh/3'-UTRlow; group D, 5'-UTRhigh/3'-UTRhigh.

 
The presence of at least one high TS expression genotype and stage III disease (survival data of patients according to tumor stage are not shown) were the adverse variables with statistical significance in the univariate analysis, which were included in the multivariate model. Both features retained an independent prognostic role for disease-free survival with 3.5 hazard ratio (HR) for high TS expression genotypes [95% confidence interval (95% CI), 2.1-4.9] and 3.9 HR for stage III disease (95% CI, 2.6-5.1); for overall survival, 2.9 HR for high TS expression genotypes (95% CI, 1.7-4.1) and 2.1 HR for stage III disease (95% CI, 1.6-4.8).


   Discussion
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Since the discovery of the VNTR polymorphism in TS5'-UTR, additional functional TS variants have been characterized and the VNTR is now studied together with a C/G single nucleotide change in the 3R allele, which produces a further distinction between 3G and 3C carriers (9, 10). The 3G allele in 5'-UTR was found to induce higher transcriptional and translational efficiency than other alleles and 3G-containing genotypes (2R/3G, 3C/3G, 3G/3G) have been correlated with high TS mRNA expression in vivo (12). Another functional TS polymorphism is a deletion/insertion of a short 6 bp sequence located in the 3'-UTR region (11). Recently, the 3'-UTR del6 allele was found to be associated with low TS mRNA stability in vitro and low TS expression in colorectal carcinomas (12, 13). In a previous investigation, we described higher TS protein expression and more aggressive phenotype of gastric carcinomas with 3R/3R genotype than tumors with 2R/3R-2R/2R genotypes (20). Now, we report the results of a global analysis of TS polymorphisms in gastric cancer patients who underwent radical surgery and fluorouracil-based adjuvant chemotherapy.

Ninety patients formed a homogeneous study population according to surgery, adjuvant therapy, and disease stage. The prognostic influence of TS5'-UTR and TS3'-UTR polymorphisms was determined in a combined analysis of high versus low TS expression genotypes. In fact, 5'-UTR and 3'-UTR variants do not share only functional influence on TS expression, but also, given their proximity, these alleles tend to be inherited together more often than would be expected by chance in a condition of linkage disequilibrium (15, 19). In the studied population, patients with 5'-UTRlow/3'-UTRlow genotypes showed the best outcome. Their disease-free survival and overall survival advantage was statistically significant in the comparison with 5'-UTRhigh/3'-UTRlow patients and 5'-UTRhigh/3'-UTRhigh patients. Patients with 5'-UTRlow/3'-UTRlow genotypes showed also a trend for better disease-free survival and overall survival than patients with 5'-UTRlow/3'-UTRhigh genotypes.

Available data support two major issues that should be focused for the interpretation of these data. Elevated TS protein levels as the results of possession of high TS expression genotypes may interfere in the mechanisms of action of fuoropyrimidines (3). Also, TS may directly promote tumor aggressiveness (21–26).

High TS expression is under investigation as a major determinant of chemoresistance to fuoropyrimidines and to fluorouracil in particular (3). The majority of studies has been done in colorectal cancer and a recent meta-analysis including 887 advanced patients and 2,610 patients with localized disease confirmed a poorer overall survival of patients with enhanced TS activity compared with cases with low TS activity (27). In gastric cancer (Table 4), some retrospective studies have investigated the prognostic role of TS expression (28–37), TS mRNA level (38–41), TS enzymatic activity (42), and TS polymorphism (20), but a significant correlation between the TS status and patients' outcome was not always detected. Notwithstanding this, TS analysis is a potential powerful predictive and prognostic tool; likely, these conflicting data suggest that standardized and reliable methods are needed to determine TS protein function and production. It is possible that the analysis of TS functional genotypes may supply more precise information and avoid potential biases of immunohistochemistry and mRNA quantification.


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  		Table 4. Studies on the prognostic role of TS status in gastric cancer

 
Immunohistochemistry implies a subjective interpretation of staining; it requires an established cutoff of positive cells and it defines a static protein status as that observed at the moment of tissue analysis. Measurements of TS mRNA expression do not account for differences in the quality of TS mRNA, which may suffer from defects in its translational efficiency and stability (10, 13). In fact, it was shown in vivo that the TS VNTR3R polymorphism may induce high TS protein expression in the absence of increased TS mRNA levels (7). Genotyping of the constitutional TS functional polymorphisms may overcome these problems and be a reliable prognostic tool. Unfortunately, this method is not free from potential biases, such as the loss of heterozygosity in the tumor. For example, germ line heterozygous 2R/3G and 3C/3G genotypes should be reclassified into 2R/loss and 3C/loss genotypes if loss of heterozygosity for the 3G allele occurred in the tumor. To date, the frequency of loss of heterozygosity for 5'-UTR3G allele and 3'-UTRdel6 allele in gastrointestinal carcinomas has not been determined yet, but this phenomenon may be relevant and it deserves further analyses.

According to recent data, the adverse prognosis of patients with high TS expression genotypes could be also related to a direct tumor-promoting effect of TS. In vitro studies support a TS binding and inhibiting activity to mRNAs of molecules critically involved in the cell cycle regulation, as p21, and apoptosis, as p53 (21–25). In a novel perspective, TS is under investigation as a potential oncogene that may contribute to tumor development and aggressiveness (25, 26).

In conclusion, further studies on the prognostic role of TS polymorphisms in gastric cancer are warranted. If confirmed in additional prospective series, the adverse effect of high TS expression genotypes may be a relevant information to improve chemotherapeutic strategies and the long-term outcome of these patients.


   Footnotes
 
Grant support: FIRB 2001 RBNE01T8C8_008 from the Italian Ministry of Scientific and Technology Research (MURST).

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 11/29/04; revised 1/28/05; accepted 2/17/05.


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