Tumor Thymidylate Synthase 1494del6 Genotype As a Prognostic Factor in Colorectal Cancer Patients Receiving Fluorouracil-Based Adjuvant Treatment

Dotor, E.; Cuatrecases, Miriam; Martínez-Iniesta, María; Navarro, Matilde; Vilardell, Felip; Guinó, Elisabet; Pareja, Laura; Figueras, Agnés; Mollevı́, David G.; Serrano, Teresa; de, Javier; Peinado, Miguel A.; Moreno, Vı́ctor; Germà, Josep R.; Capellà, Gabriel; Villanueva, Alberto

doi:10.1200/jco.2005.03.5253

Cited by 117 publications

(71 citation statements)

References 33 publications

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“…On this basis, our findings of nonsignificantly increased CRA risks in low-expression genotype groups, when categorised either by TSER genotype alone or in combination with the 3R G/C polymorphism, is seemingly at odds with the reduced CRA risk in individuals homozygous for the TS 1494del6 variant. More recent data, however, indicate that functional predictions based on in vitro tests may not reflect the real situation in vivo (Etienne et al, 2002;Jakobsen et al, 2005;Dotor et al, 2006). For example, while studies have reported increased TS mRNA expression in human colorectal tumours from individuals with 3R/3R genotype, the only study of TS protein activity reported an increased activity in tumours harbouring the 3R/2R genotype, indicating the existence of additional posttranscriptional regulatory pathways (Etienne et al, 2002).…”

Section: Discussionmentioning

confidence: 87%

“…Presence of the deleted allele has been reported to result in enhanced TS mRNA degradation in vitro, and two clinical studies have observed reduced TS mRNA expression in colorectal tumours of del/del homozygote patients (Lenz et al, 2002;Mandola et al, 2004). In a recent study of CRC patients receiving 5-fluorouracil (5-FU)-based adjuvant chemotherapy, patients heterozygous or homozygous for the deleted allele had an improved survival indicating likely increased sensitivity to TS inhibition, providing further evidence that this polymorphism is functional (Dotor et al, 2006). Furthermore, the largest previous case -control study investigating the association of TS 1494del6 genotype and colorectal neoplasia risk, reported a reduced CRC risk in women homozygous for the deleted allele (Ulrich et al, 2005).…”

Section: Discussionmentioning

confidence: 97%

“…For example, while studies have reported increased TS mRNA expression in human colorectal tumours from individuals with 3R/3R genotype, the only study of TS protein activity reported an increased activity in tumours harbouring the 3R/2R genotype, indicating the existence of additional posttranscriptional regulatory pathways (Etienne et al, 2002). Additionally, two recent studies of 5-FU chemotherapy in patients with CRC, one in the adjuvant setting and one in patients with metastatic disease, both reported significantly improved outcomes in individuals with 3R/3R genotype (Jakobsen et al, 2005;Dotor et al, 2006). Thus prediction of TS protein activity in either normal or tumour tissue based on TS polymorphism genotypes is far from straightforward, and discrepancies in associations between colorectal neoplasia risk and TS genotypes with apparently similar functional effects are not uncommon (Ulrich et al, 2002(Ulrich et al, , 2005Adleff et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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Thymidylate synthase polymorphisms, folate and B-vitamin intake, and risk of colorectal adenoma

et al. 2007

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The effects of polymorphisms in genes coding for key folate metabolism enzymes such as thymidylate synthetase (TS) on colorectal neoplasia risk are likely to be influenced by gene -gene and gene -nutrient interactions. We investigated the combined effects of three polymorphisms in the TS gene region, TSER, TS 3R G4C, and TS 1494del6, dietary intakes of folate and other B vitamins, and genotype for other folate metabolism variants, in a colorectal adenoma (CRA) case -control study. Individuals homozygous for TS 1494del6 del/del were at significantly reduced CRA risk compared to those with either ins/del or ins/ins genotypes (odds ratio 0.52; 95% confidence interval: 0.31 -0.85, P ¼ 0.009). We also observed evidence of interactions between TS 1494del6 genotype and intake of folate, and vitamins B 6 and B 12 , and MTHFR C677T genotype, with the reduction in risk in del/del homozygotes being largely confined to individuals with high nutrient intakes and MTHFR 677CC genotype (P interaction ¼ 0.01, 0.006, 0.03, and 0.07, respectively). TSER genotype, when considered either alone or in combination with TS 3R G4C genotype, did not significantly influence CRA risk. These findings support a role for TS in colorectal carcinogenesis, and provide further evidence that functional polymorphisms in folate metabolism genes act as low-risk alleles for colorectal neoplasia and participate in complex gene -gene and gene -nutrient interactions.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Thymidylate synthase polymorphisms, folate and B-vitamin intake, and risk of colorectal adenoma

et al. 2007

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“…A Ruzzo et al influent managements for patients with metastatic disease, 32 or the lack of multivariate analysis for modeling marginally significant survival associations. 33 We found a biologically plausible association between TS 3 0 -UTR 6 þ /6 þ genotype and adverse PFS.…”

Section: Folfiri Pharmacogenetics In Colorectal Cancermentioning

confidence: 99%

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy

et al. 2007

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The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3 0 -UTR 6 þ /6 þ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval ¼ 1.56-5.80; P ¼ 0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III-IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.

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“…28 The À6 bp allele (152 bp) and the þ 6 bp allele (158 bp) were identified after 8% polyacrylamide gel electrophoresis and ethidium bromide staining.…”

Section: Ts Genotyping Assaysmentioning

confidence: 99%

Transcription factor-binding sites in the thymidylate synthase gene: predictors of outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin?

et al. 2007

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The identification of clinical and genetic parameters to predict the outcome in advanced colorectal cancer is a key issue in the management of this disease. We ascertained whether the clinical determinants of survival defined in a large cohort of patients treated with 5-fluorouracil (5-FU) (European Organization for the Research and Treatment of Cancer, EORTC model) also apply to 109 colorectal cancer patients receiving a therapy including oxaliplatin/5-FU as their first-line treatment. Our results confirm the considerable discriminatory power of the clinical model proposed in patients treated with a combined chemotherapy regimen. With the aim of identifying additional genetic prognostic parameters, we determined whether the polymorphisms in the promoter region of the thymidylate synthase (TS) gene that modifies the number of operative binding sites of a transcription factor (USF) could predict the clinical outcome of our patients and complement the EORTC clinical model. Our results indicate that this new genetic parameter (the number of USF-binding sites) could be considered when evaluating the role of TS genotype in the efficacy of the 5-FU-based regimens. Further, confirmatory studies aimed at evaluating the effect of the number of binding sites of transcription factors for selecting 5-FU-treated patients are warranted.

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Tumor Thymidylate Synthase 1494del6 Genotype As a Prognostic Factor in Colorectal Cancer Patients Receiving Fluorouracil-Based Adjuvant Treatment

Abstract: Tumor TS 1494del6 genotype may be a prognostic factor in FU-based adjuvant treatment of colorectal cancer patients.

Cited by 117 publications

References 33 publications

Thymidylate synthase polymorphisms, folate and B-vitamin intake, and risk of colorectal adenoma

Thymidylate synthase polymorphisms, folate and B-vitamin intake, and risk of colorectal adenoma

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy

Transcription factor-binding sites in the thymidylate synthase gene: predictors of outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin?

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