A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation

Salvatore Terrazzino, Marco Agostini, Salvatore Pucciarelli, Lara Maria Pasetto, Maria Luisa Friso, Alessandro Ambrosi, Veronica Lisi, Alberta Leon, Mario Lise, Donato Nitti

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE: The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter, namely the variable number tandem repeat polymorphism (TS VNTR) and the intrarepeat G to C single nucleotide polymorphism (TS SNP), are predictive markers of tumor regression in rectal cancer patients following preoperative chemoradiotherapy. BASIC METHODS: Blood samples from 125 patients with primary adenocarcinoma of the mid-low rectum who received 5-fluorouracil-based chemotherapy and external beam radiotherapy (median dose 48.4 Gy), 125 patients (women n=45, men n=80; median age 60 years, range 31-79 years) were genotyped. Response to preoperative treatment was evaluated employing the Tumor Regression Grade criteria. On the basis of the pathologic response, patients were classified as responders (TRG 1-2, n=48) and non-responders (TRG 3-5, n=74). Three patients were excluded because of insufficient data. MAIN RESULTS: Among the polymorphic variants examined, the MTHFR 677T-1298A haplotype was, upon univariate analysis, the only variable found associated with tumor regression (P=0.004). Moreover, at multivariate analysis, the MTHFR 677T-1298A haplotype was an independent predictor of tumor regression. Patients not carrying the MTHFR 677T-1298A haplotype (odds ratio 0.29, 95% confidence interval 0.13-0.64, P=0.002) displayed a higher response rate than patients with the MTHFR 677T-1298A haplotype. CONCLUSIONS: Unlike TS VNTR and SNP polymorphisms, MTHFR 677T-1298A haplotype in genomic DNA has the potential to be a predictive marker of tumor response in rectal cancer patients submitted to preoperative chemoradiotherapy

Original languageEnglish
Pages (from-to)817-824
Number of pages8
JournalPharmacogenetics and Genomics
Volume16
Issue number11
DOIs
Publication statusPublished - Nov 2006

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Methylenetetrahydrofolate Reductase (NADPH2)
Rectal Neoplasms
Haplotypes
Genes
Neoplasms
Single Nucleotide Polymorphism
Chemoradiotherapy
Tumor Biomarkers
Thymidylate Synthase
Minisatellite Repeats
Rectum
Fluorouracil
Adenocarcinoma
Radiotherapy
Multivariate Analysis
Odds Ratio
Confidence Intervals
Drug Therapy
DNA

Keywords

  • Germline polymorphisms
  • MTHFR haplotype
  • Preoperative chemoradiation
  • Rectal cancer
  • Tumor regression grade

ASJC Scopus subject areas

  • Genetics
  • Pharmacology

Cite this

A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation. / Terrazzino, Salvatore; Agostini, Marco; Pucciarelli, Salvatore; Pasetto, Lara Maria; Friso, Maria Luisa; Ambrosi, Alessandro; Lisi, Veronica; Leon, Alberta; Lise, Mario; Nitti, Donato.

In: Pharmacogenetics and Genomics, Vol. 16, No. 11, 11.2006, p. 817-824.

Research output: Contribution to journalArticle

Terrazzino, S, Agostini, M, Pucciarelli, S, Pasetto, LM, Friso, ML, Ambrosi, A, Lisi, V, Leon, A, Lise, M & Nitti, D 2006, 'A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation', Pharmacogenetics and Genomics, vol. 16, no. 11, pp. 817-824. https://doi.org/10.1097/01.fpc.0000230412.89973.c0
Terrazzino, Salvatore ; Agostini, Marco ; Pucciarelli, Salvatore ; Pasetto, Lara Maria ; Friso, Maria Luisa ; Ambrosi, Alessandro ; Lisi, Veronica ; Leon, Alberta ; Lise, Mario ; Nitti, Donato. / A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation. In: Pharmacogenetics and Genomics. 2006 ; Vol. 16, No. 11. pp. 817-824.
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abstract = "OBJECTIVE: The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter, namely the variable number tandem repeat polymorphism (TS VNTR) and the intrarepeat G to C single nucleotide polymorphism (TS SNP), are predictive markers of tumor regression in rectal cancer patients following preoperative chemoradiotherapy. BASIC METHODS: Blood samples from 125 patients with primary adenocarcinoma of the mid-low rectum who received 5-fluorouracil-based chemotherapy and external beam radiotherapy (median dose 48.4 Gy), 125 patients (women n=45, men n=80; median age 60 years, range 31-79 years) were genotyped. Response to preoperative treatment was evaluated employing the Tumor Regression Grade criteria. On the basis of the pathologic response, patients were classified as responders (TRG 1-2, n=48) and non-responders (TRG 3-5, n=74). Three patients were excluded because of insufficient data. MAIN RESULTS: Among the polymorphic variants examined, the MTHFR 677T-1298A haplotype was, upon univariate analysis, the only variable found associated with tumor regression (P=0.004). Moreover, at multivariate analysis, the MTHFR 677T-1298A haplotype was an independent predictor of tumor regression. Patients not carrying the MTHFR 677T-1298A haplotype (odds ratio 0.29, 95{\%} confidence interval 0.13-0.64, P=0.002) displayed a higher response rate than patients with the MTHFR 677T-1298A haplotype. CONCLUSIONS: Unlike TS VNTR and SNP polymorphisms, MTHFR 677T-1298A haplotype in genomic DNA has the potential to be a predictive marker of tumor response in rectal cancer patients submitted to preoperative chemoradiotherapy",
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T1 - A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation

AU - Terrazzino, Salvatore

AU - Agostini, Marco

AU - Pucciarelli, Salvatore

AU - Pasetto, Lara Maria

AU - Friso, Maria Luisa

AU - Ambrosi, Alessandro

AU - Lisi, Veronica

AU - Leon, Alberta

AU - Lise, Mario

AU - Nitti, Donato

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N2 - OBJECTIVE: The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter, namely the variable number tandem repeat polymorphism (TS VNTR) and the intrarepeat G to C single nucleotide polymorphism (TS SNP), are predictive markers of tumor regression in rectal cancer patients following preoperative chemoradiotherapy. BASIC METHODS: Blood samples from 125 patients with primary adenocarcinoma of the mid-low rectum who received 5-fluorouracil-based chemotherapy and external beam radiotherapy (median dose 48.4 Gy), 125 patients (women n=45, men n=80; median age 60 years, range 31-79 years) were genotyped. Response to preoperative treatment was evaluated employing the Tumor Regression Grade criteria. On the basis of the pathologic response, patients were classified as responders (TRG 1-2, n=48) and non-responders (TRG 3-5, n=74). Three patients were excluded because of insufficient data. MAIN RESULTS: Among the polymorphic variants examined, the MTHFR 677T-1298A haplotype was, upon univariate analysis, the only variable found associated with tumor regression (P=0.004). Moreover, at multivariate analysis, the MTHFR 677T-1298A haplotype was an independent predictor of tumor regression. Patients not carrying the MTHFR 677T-1298A haplotype (odds ratio 0.29, 95% confidence interval 0.13-0.64, P=0.002) displayed a higher response rate than patients with the MTHFR 677T-1298A haplotype. CONCLUSIONS: Unlike TS VNTR and SNP polymorphisms, MTHFR 677T-1298A haplotype in genomic DNA has the potential to be a predictive marker of tumor response in rectal cancer patients submitted to preoperative chemoradiotherapy

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KW - Germline polymorphisms

KW - MTHFR haplotype

KW - Preoperative chemoradiation

KW - Rectal cancer

KW - Tumor regression grade

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