Polymorphism in the Thymidylate Synthase Promoter Enhancer Region Is Not an Efficacious Marker for Tumor Sensitivity to 5-Fluorouracil-based Oral Adjuvant Chemotherapy in Colorectal Cancer

• Published in: Clinical cancer research Vol. 9; no. 10; pp. 3700 - 3704
• Main Authors: TSUJI, Takashi, HIDAKA, Shigekazu, SHIBASAKI, Shinichi, NANASHIMA, Atsushi, YAMAGUCHI, Hiroyuki, YASUTAKE, Tohru, TAGAWA, Yutaka, SAWAI, Terumitsu, NAKAGOE, Tohru, YANO, Hiroshi, HASEBA, Masatoshi, KOMATSU, Hideaki, SHINDOU, Hisakazu, FUKUOKA, Hidetoshi, YOSHINAGA, Megumi
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2003
• Subjects: Administration, Oral; Aged; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor; Chemotherapy; Chemotherapy, Adjuvant; Colorectal Neoplasms - genetics; Disease-Free Survival; Female; Fluorouracil - pharmacology; Genotype; Humans; Male; Medical sciences; Middle Aged; Multivariate Analysis; Pharmacology. Drug treatments; Polymerase Chain Reaction; Polymorphism, Genetic; Prognosis; Promoter Regions, Genetic; Regression Analysis; Thymidylate Synthase - genetics; Time Factors; Treatment Outcome; Antineoplastic agent; Rectal disease; Transcription promoter; Adjuvant treatment; Biological marker; Molecular epidemiology; Genetics; Intestinal disease; Colon; Fluorouracil; Human; Nucleotide sequence; Enzyme; Transferases; Fluoropyrimidine derivatives; Oral administration; Genotype; Malignant tumor; Thymidylate synthase; Colonic disease; Allele; Chemotherapy; Sensitivity resistance; Treatment; Methyltransferases; Rectum; Digestive diseases; Pyrimidine derivatives; Polymorphism
• ISSN: 1078-0432; 1557-3265

Thymidylate synthase (TS) is the target enzyme of 5-fluoropyrimidines. The TS gene promoter enhancer region (TSER) possesses tandem, repeated, regulatory sequences that are polymorphic in humans. This polymorphism has been reported to influence TS expression in vitro and in vivo . In this study, we assessed whether or not the TSER genotype is an efficacious marker for tumor sensitivity to 5-fluorouracil (5-FU)-based oral adjuvant chemotherapy for colorectal cancer. One hundred and thirty-five Japanese patients who received curative resection and 5-FU-based oral adjuvant chemotherapy were studied. TSER genotypes of the tumors were analyzed by PCR. The numbers of repeated sequences of representative bands were determined by direct sequence. The genotypes of two-/two-repeats ( TSER 2/2), two-/three-repeats ( TSER 2/3), three-/three-repeats ( TSER 3/3), and three-/five-repeats ( TSER 3/5) were found in 11 (8.1%), 32 (23.7%), 85 (63.0%), and 7 (5.2%) tumors, respectively. Patients were classified into two groups: TSER 2/2 or 2/3 group; and the TSER 3/3 group. The relationship between the TSER genotype group and disease-free intervals was analyzed by univariate and multivariate analyses. Five-year disease-free survivals of the TSER 2/2 or 2/3 group and the TSER 3/3 group were 77% and 75%, respectively ( P = 0.89). Multivariate analysis revealed that stage was the only independent prognostic factor and that the TSER genotype did not have a prognostic significance (hazard ratio for TSER 3/3, 0.91; P = 0.84). In conclusion, TSER genotype is not an efficacious marker for tumor sensitivity to 5-FU-based oral adjuvant chemotherapy for Japanese colorectal cancer patients after curative resection.