Effect of methylenetetrahydrofolate reductase 677C→T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients

Giuseppe Toffoli, Antonio Russo, Federico Innocenti, Giuseppe Corona, Salvatore Tumolo, Franca Sartor, Enrico Mini, Mauro Boiocchi

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

MTHFR is a critical enzyme that regulates the metabolism of folate and methionine, both of which are important factors in DNA methylation and synthesis. Subjects with the 677C→T variant have impaired remethylation of Hcy to methionine that could determine hyperhomocysteinemia. Remethylation of Hcy into methionine and DNA methylation are also affected by MTX treatment. Thus, a combined effect between MTX and reduced activity of the MTHFR 677C→T polymorphism could occur, leading to toxicity. In a clinical trial, 43 ovarian cancer patients were treated with low doses of MTX. During MTX therapy, 12 patients (27.9%) developed G3/4 WHO toxicity. In these 12 patients, we observed 6 G3/4 thrombocytopenias, 1 G3 neutropenia, 1 G3 anemia, 9 G3 mucositis cases and 1 G4 mucositis case. A significant association was observed between toxicity and TT MTHFR 677 genotype (p <0.0001). G3/4 toxicity occurred in 10 of 13 (77%), 1 of 17 (6%) and 1 of 13 (8%) patients with the TT, CT and CC MTHFR genotypes, respectively. According to the logistic regression model, patients with the TT genotype had a relative risk of 42.0 (95% Cl 4.2-418.6) of developing G3/4 toxicity compared to patients with the CC and CT genotypes. Patients with the TT genotype had Hcy plasma levels after MTX therapy significantly (p = 0.0001) higher than basal levels (mean ± SD = 16.71 ± 4.72 vs. 12.48 ± 3.57 μmol/l); moreover, they also had higher Hcy plasma levels after MTX than patients with other MTHFR 677 genotypes (CC mean ± SD = 9.87 ± 3.61 μmol/l and CT mean ± SD = 11.48 ± 3.13 μmol/l). Finally, significant associations were observed between G3/4 WHO toxicity and higher Hcy plasma levels after MTX treatment (p = 0.0004). In conclusion, our data suggest that the TT MTHFR 677 genotype is associated with marked MTX-induced hyperhomocysteinemia and could represent a pharmacogenetic marker for toxicity after chronic treatment with low doses of MTX. £ 2002 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)294-299
Number of pages6
JournalInternational Journal of Cancer
Volume103
Issue number3
DOIs
Publication statusPublished - Jan 20 2003

Fingerprint

Methylenetetrahydrofolate Reductase (NADPH2)
Homocysteine
Methotrexate
Ovarian Neoplasms
Genotype
Methionine
Hyperhomocysteinemia
Mucositis
DNA Methylation
Therapeutics
Logistic Models
Fibroblast Growth Factors
Pharmacogenetics
Neutropenia
Folic Acid
Anemia
Clinical Trials
Enzymes

Keywords

  • Homocysteine
  • Methotrexate
  • Methylenetetrahydrofolate reductase
  • Ovarian cancer
  • Pharmacogenetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Effect of methylenetetrahydrofolate reductase 677C→T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients. / Toffoli, Giuseppe; Russo, Antonio; Innocenti, Federico; Corona, Giuseppe; Tumolo, Salvatore; Sartor, Franca; Mini, Enrico; Boiocchi, Mauro.

In: International Journal of Cancer, Vol. 103, No. 3, 20.01.2003, p. 294-299.

Research output: Contribution to journalArticle

@article{dba532cdb6a146c7a8666cdfec1d34bc,
title = "Effect of methylenetetrahydrofolate reductase 677C→T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients",
abstract = "MTHFR is a critical enzyme that regulates the metabolism of folate and methionine, both of which are important factors in DNA methylation and synthesis. Subjects with the 677C→T variant have impaired remethylation of Hcy to methionine that could determine hyperhomocysteinemia. Remethylation of Hcy into methionine and DNA methylation are also affected by MTX treatment. Thus, a combined effect between MTX and reduced activity of the MTHFR 677C→T polymorphism could occur, leading to toxicity. In a clinical trial, 43 ovarian cancer patients were treated with low doses of MTX. During MTX therapy, 12 patients (27.9{\%}) developed G3/4 WHO toxicity. In these 12 patients, we observed 6 G3/4 thrombocytopenias, 1 G3 neutropenia, 1 G3 anemia, 9 G3 mucositis cases and 1 G4 mucositis case. A significant association was observed between toxicity and TT MTHFR 677 genotype (p <0.0001). G3/4 toxicity occurred in 10 of 13 (77{\%}), 1 of 17 (6{\%}) and 1 of 13 (8{\%}) patients with the TT, CT and CC MTHFR genotypes, respectively. According to the logistic regression model, patients with the TT genotype had a relative risk of 42.0 (95{\%} Cl 4.2-418.6) of developing G3/4 toxicity compared to patients with the CC and CT genotypes. Patients with the TT genotype had Hcy plasma levels after MTX therapy significantly (p = 0.0001) higher than basal levels (mean ± SD = 16.71 ± 4.72 vs. 12.48 ± 3.57 μmol/l); moreover, they also had higher Hcy plasma levels after MTX than patients with other MTHFR 677 genotypes (CC mean ± SD = 9.87 ± 3.61 μmol/l and CT mean ± SD = 11.48 ± 3.13 μmol/l). Finally, significant associations were observed between G3/4 WHO toxicity and higher Hcy plasma levels after MTX treatment (p = 0.0004). In conclusion, our data suggest that the TT MTHFR 677 genotype is associated with marked MTX-induced hyperhomocysteinemia and could represent a pharmacogenetic marker for toxicity after chronic treatment with low doses of MTX. £ 2002 Wiley-Liss, Inc.",
keywords = "Homocysteine, Methotrexate, Methylenetetrahydrofolate reductase, Ovarian cancer, Pharmacogenetics",
author = "Giuseppe Toffoli and Antonio Russo and Federico Innocenti and Giuseppe Corona and Salvatore Tumolo and Franca Sartor and Enrico Mini and Mauro Boiocchi",
year = "2003",
month = "1",
day = "20",
doi = "10.1002/ijc.10847",
language = "English",
volume = "103",
pages = "294--299",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "3",

}

TY - JOUR

T1 - Effect of methylenetetrahydrofolate reductase 677C→T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients

AU - Toffoli, Giuseppe

AU - Russo, Antonio

AU - Innocenti, Federico

AU - Corona, Giuseppe

AU - Tumolo, Salvatore

AU - Sartor, Franca

AU - Mini, Enrico

AU - Boiocchi, Mauro

PY - 2003/1/20

Y1 - 2003/1/20

N2 - MTHFR is a critical enzyme that regulates the metabolism of folate and methionine, both of which are important factors in DNA methylation and synthesis. Subjects with the 677C→T variant have impaired remethylation of Hcy to methionine that could determine hyperhomocysteinemia. Remethylation of Hcy into methionine and DNA methylation are also affected by MTX treatment. Thus, a combined effect between MTX and reduced activity of the MTHFR 677C→T polymorphism could occur, leading to toxicity. In a clinical trial, 43 ovarian cancer patients were treated with low doses of MTX. During MTX therapy, 12 patients (27.9%) developed G3/4 WHO toxicity. In these 12 patients, we observed 6 G3/4 thrombocytopenias, 1 G3 neutropenia, 1 G3 anemia, 9 G3 mucositis cases and 1 G4 mucositis case. A significant association was observed between toxicity and TT MTHFR 677 genotype (p <0.0001). G3/4 toxicity occurred in 10 of 13 (77%), 1 of 17 (6%) and 1 of 13 (8%) patients with the TT, CT and CC MTHFR genotypes, respectively. According to the logistic regression model, patients with the TT genotype had a relative risk of 42.0 (95% Cl 4.2-418.6) of developing G3/4 toxicity compared to patients with the CC and CT genotypes. Patients with the TT genotype had Hcy plasma levels after MTX therapy significantly (p = 0.0001) higher than basal levels (mean ± SD = 16.71 ± 4.72 vs. 12.48 ± 3.57 μmol/l); moreover, they also had higher Hcy plasma levels after MTX than patients with other MTHFR 677 genotypes (CC mean ± SD = 9.87 ± 3.61 μmol/l and CT mean ± SD = 11.48 ± 3.13 μmol/l). Finally, significant associations were observed between G3/4 WHO toxicity and higher Hcy plasma levels after MTX treatment (p = 0.0004). In conclusion, our data suggest that the TT MTHFR 677 genotype is associated with marked MTX-induced hyperhomocysteinemia and could represent a pharmacogenetic marker for toxicity after chronic treatment with low doses of MTX. £ 2002 Wiley-Liss, Inc.

AB - MTHFR is a critical enzyme that regulates the metabolism of folate and methionine, both of which are important factors in DNA methylation and synthesis. Subjects with the 677C→T variant have impaired remethylation of Hcy to methionine that could determine hyperhomocysteinemia. Remethylation of Hcy into methionine and DNA methylation are also affected by MTX treatment. Thus, a combined effect between MTX and reduced activity of the MTHFR 677C→T polymorphism could occur, leading to toxicity. In a clinical trial, 43 ovarian cancer patients were treated with low doses of MTX. During MTX therapy, 12 patients (27.9%) developed G3/4 WHO toxicity. In these 12 patients, we observed 6 G3/4 thrombocytopenias, 1 G3 neutropenia, 1 G3 anemia, 9 G3 mucositis cases and 1 G4 mucositis case. A significant association was observed between toxicity and TT MTHFR 677 genotype (p <0.0001). G3/4 toxicity occurred in 10 of 13 (77%), 1 of 17 (6%) and 1 of 13 (8%) patients with the TT, CT and CC MTHFR genotypes, respectively. According to the logistic regression model, patients with the TT genotype had a relative risk of 42.0 (95% Cl 4.2-418.6) of developing G3/4 toxicity compared to patients with the CC and CT genotypes. Patients with the TT genotype had Hcy plasma levels after MTX therapy significantly (p = 0.0001) higher than basal levels (mean ± SD = 16.71 ± 4.72 vs. 12.48 ± 3.57 μmol/l); moreover, they also had higher Hcy plasma levels after MTX than patients with other MTHFR 677 genotypes (CC mean ± SD = 9.87 ± 3.61 μmol/l and CT mean ± SD = 11.48 ± 3.13 μmol/l). Finally, significant associations were observed between G3/4 WHO toxicity and higher Hcy plasma levels after MTX treatment (p = 0.0004). In conclusion, our data suggest that the TT MTHFR 677 genotype is associated with marked MTX-induced hyperhomocysteinemia and could represent a pharmacogenetic marker for toxicity after chronic treatment with low doses of MTX. £ 2002 Wiley-Liss, Inc.

KW - Homocysteine

KW - Methotrexate

KW - Methylenetetrahydrofolate reductase

KW - Ovarian cancer

KW - Pharmacogenetics

UR - http://www.scopus.com/inward/record.url?scp=0037454801&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037454801&partnerID=8YFLogxK

U2 - 10.1002/ijc.10847

DO - 10.1002/ijc.10847

M3 - Article

C2 - 12471611

AN - SCOPUS:0037454801

VL - 103

SP - 294

EP - 299

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 3

ER -