Glutathione S-transferase P1 Ile105Val polymorphism is associated with haematological toxicity in elderly rectal cancer patients receiving preoperative chemoradiotherapy.
BACKGROUND
Increasing evidence suggests that common gene polymorphisms may influence the toxicity of various cytotoxic agents used in the treatment of cancer.


OBJECTIVE
To evaluate the predictive value of acute toxicity of methylenetetrahydrofolate reductase 677T polymorphism, glutathione S-transferase P1 (GSTP1) substitution of isoleucine with valine at codon 105 (Ile105Val) polymorphism and the tandem repeat polymorphism in the thymidylate synthase gene promoter in elderly patients with rectal cancer receiving preoperative chemoradiotherapy (CRT).


METHODS
From 1994 to 2002, 166 Caucasian patients underwent surgery following CRT for mid-low rectal cancer at a single institution, 42 (male-to-female ratio, 25 : 17) of whom were aged > or =65 years (median age 70 years, range 65-79). The pre-treatment clinical stage was tumour (T) stage 3-4 in 38 patients and node (N)-positive in 29 patients. Patients received external-beam radiotherapy with conventional fractionation and fluorouracil-based chemotherapy. Blood samples were used to extract and amplify DNA. Gene polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion. Acute toxicity to preoperative therapy was reported according to the National Cancer Institute Common Toxicity Criteria, version 2. Univariate and multivariate analyses were performed using one-way analysis of variance and linear regression, respectively.


RESULTS
Haematological toxicity (grade 1-2) was observed in 15 of 40 patients for whom toxicity data were available and gastrointestinal toxicity (grade 1-4) in 24 of these same 40 patients. At univariate analysis, female sex (p = 0.036) and GSTP1 Ile105Val (p = 0.0376) were associated with haematological toxicity. At multivariate analysis, GSTP1 Ile105Val polymorphism (p = 0.041) was the only factor found to be associated with haematological toxicity. Patients carrying the Val/Val genotype in the GSTP1 gene had a lower risk of haematological toxicity (odds ratio = 0.322, 95% CI 0.101, 0.957) than patients with the Ile/Ile genotype.


CONCLUSIONS
GSTP1 Ile105Val polymorphism is a promising marker of potential haematological toxicity in elderly patients with rectal cancer receiving preoperative CRT.
Clinica Chirurgica II, Department of Oncological and Surgical Sciences, Universita di Padova, Via Giustiniani 2, Padova, Italy.
Marco
M
Agostini
Lara Maria
LM
Pasetto
Salvatore
S
Pucciarelli
Salvatore
S
Terrazzino
Alessandro
A
Ambrosi
Chiara
C
Bedin
Francesca
F
Galdi
Maria Luisa
ML
Friso
Claudia
C
Mescoli
Emanuele
E
Urso
Alberta
A
Leon
Mario
M
Lise
Donato
D
Nitti
D000230:Adenocarcinoma / Q000628:therapy*; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006402:Hematologic Diseases / Q000209:etiology / Q000235:genetics; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects; D012004:Rectal Neoplasms / Q000628:therapy*; D015183:Restriction Mapping; D012737:Sex Factors; D013940:Thymidylate Synthase / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005472:Fluorouracil