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Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 7230-7231 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.0495
Studying the Predictive/Prognostic Role of Thymidylate Synthase Genotypes in Patients With Colorectal Cancer: Is One Polymorphism Enough?
Medical Oncology Unit, Hospital of Urbino, Urbino, Italy To the Editor: We read with interest the recently published study by Jakobsen et al1 on the favorable predictive/prognostic effect in metastatic colorectal cancer of the three-repeat, variable number of tandem repeats (VNTR) polymorphism in Thymidylate Synthase (TS), 5'untranslated region (5'-UTR). In our opinion, some observations are worth mentioning. TS 5'-UTR VNTR consists of either a two or three 28-bp repeated sequence (2R or 3R alleles).2 The 3R allele has been related to enhanced mRNA translational efficiency and high TS expression when compared to the 2R allele.2 The greatest effect was observed in the presence of the homozygous 3R/3R genotype.2 A G/C polymorphism within the 3R VNTR was found to produce two additional alleles (3G or 3C) at this locus.3,4 In vitro, the 3G allele has been associated with higher reporter gene activity at both DNA transcriptional and mRNA translational levels than the 3C allele.3,4 In vivo, 3G-containing genotypes (2R/3G, 3C/3G, 3G/3G) showed correlation with high TS mRNA expression.5 According to this finding, 5'-UTR 3C/3G, 3G/3G high TS expression genotypes and 5'-UTR 3C/3C low TS expression genotype can be distinguished among carriers of the VNTR 5'-UTR 3R/3R genotype. Similarly, former heterozygous 5'-UTR 2R/3R genotype, (low TS expression with respect to 3R/3R genotype) could be reclassified into 5'-UTR 2R/3G high and 5'-UTR 2R/3C low TS expression genotypes.5,6 In a recent report including 134 gastric cancer patients,6 we found that among 38 patients with TS 5'-UTR 3R/3R genotype there were 31 patients with TS 5'-UTR 3G/3C or 3G/3G genotypes and 7 patients with TS 5'-UTR 3C/3C genotype. Among 76 patients with heterozygous TS 5'-UTR 2R/3R genotype, 42 patients showed TS 5'-UTR 2R/3G genotype and 34 patients showed TS 5'-UTR 2R/3C genotype. On the whole, the simple assessment of TS 5'-UTR VNTR identified 28% carriers of the 3R/3R high TS expression genotype and 72% carriers of low TS expression genotypes (3R/2R or 2R/2R). After genotyping the G/C polymorphism in 3R alleles, there was a shift toward 55% carriers of high TS expression genotypes (3G/3G, 3G/3C, 2R/3G) and 45% carriers of low TS expression genotypes (3C/3C, 2R/3C, 2R/2R). By adopting this categorization, an adverse prognosis of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy was found in carriers of TS 5'-UTR 3G/3G, 3G/3C, 2R/3G genotypes.7 The analysis of the predictive/prognostic role of TS polymorphisms in patients receiving fluorouracil may be even more complex if we consider an additional 6-bp deletion/insertion polymorphism (del6 or ins6 alleles) at position 1494 in the TS 3'-untranslated region (3'-UTR).2 Recent findings indicate that the TS 3'-UTRdel6 allele may determine low TS mRNA stability and low TS expression in comparison with TS 3'-UTRins6 allele.8 Colorectal carcinomas with ins6/ins6 genotype showed a trend for higher TS mRNA levels than tumors with del6/del6 genotype.5 TS polymorphisms, which underlie high TS expression, are likely to be related to fluorouracil chemoresistance and adverse prognosis.9 One of the potential reasons for the opposite findings by Jakobsen et al1 is the lacking analysis of the TS 5'-UTR G/C polymorphism within 3R VNTR and the lack of combined analysis of TS 5'-UTR and TS 3'-UTR genotypes. Disappointingly, Jakobsen et al1 did not plan these assessments and they did not comment on these issues in the discussion. In our opinion, studies on TS polymorphisms in cancer pharmacogenomics should consider the global evaluation of combined VNTR-G/C polymorphisms in TS 5'-UTR and del6/ins6 in TS 3'-UTR. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Jakobsen A, Nielsen JN, Gyldenkerne N, et al: Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J Clin Oncol 23:1365-1369, 2005 2. Kawakami K: Thymidylate synthase gene in pharmacogenetics. Curr Pharmacogenomics 2:137-147, 2004[CrossRef]
3. Kawakami K, Watanabe G: Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of the thymidylate synthase gene. Cancer Res 63:6004-6007, 2003
4. Mandola MV, Stoehlmacher J, Muller-Weeks S, et al: 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 63:2898-2904, 2003 5. Kawakami K, Watanabe G: The association of thymidylate synthase mRNA expression with its three gene polymorphisms in colorectal cancer. Proc Am Assoc Cancer Res 45, 2004 (abstr 2104) 6. Graziano F, Kawakami K, Watanabe G, et al: Association of thymidylate synthase polymorphisms with gastric cancer susceptibility. Int J Cancer 112:1010-1014, 2004[CrossRef][Medline]
7. Kawakami K, Graziano F, Watanabe G, et al: Prognostic role of Thymidylate Synthase polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy. Clin Cancer Res 11:3778-3783, 2005 8. Mandola MV, Stoehlmacher J, Zhang W, et al: A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 14:319-327, 2004[CrossRef][Medline]
9. Popat S, Matakidou A, Houlston RS: Thymidylate synthase expression and prognosis in colorectal cancer: A systematic review and meta-analysis. J Clin Oncol 22:529-536, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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