title: Loss of heterozygosity at the thymidylate synthase (TS) locus on chromosome 18 affects tumor response and survival in individuals heterozygous for a 28-bp polymorphism in the TS gene.
abstract: Thymidylate synthase (TS), the target enzyme of the fluoropyrimidine class of drugs, has a 28-bp repeat polymorphism in the promoter region that has been associated with response of tumors to 5-fluorouracil-based therapy. Patients homozygous for the double repeat (2R/2R) in the TS gene have an overall better outcome from treatment than patients homozygous for the triple repeat (3R/3R). However, due to loss of heterozygosity at the TS locus on chromosome 18 in cancer cells, heterozygous 2R/3R individuals can acquire the 2R/loss or the 3R/loss genotype in their tumors. The purpose of this study was to determine whether the response of colorectal cancer to fluoropyrimidine therapy is associated with the resulting tumor TS genotype when loss of heterozygosity occurs in tumor DNA. A total of 30 colorectal cancer patients treated with the fluoropyrimidine-based combination S-1, all of whom had stage IV disease, were studied. The response rate to S-1 in this group of patients was 13 of 30 (43%). The heterozygous 2R/3R genotype was found in 22 of 30 normal tissues, whereas 10 (45%) of the matched cancer tissues showed only the 2R-sequence band (2R/loss), and 7 cancer tissues (32%) showed only the 3R-sequence band (3R/loss). The response rate of the 2R/loss tumor genotype patients was 80% (8 of 10) compared with 14% (1 of 7) in the 3R/loss genotype group (P = 0.029). Patients with tumor 3R/loss genotypes had significantly lower survival than 2R/loss genotypes. Heterozygous patients with a 2R/loss tumor genotype had the same survival as 2R/2R patients, whereas patients with a 2R/3R tumor genotype had a short survival similar to homozygous 3R/3R genotypes. These results show that: (a) response to 5-fluorouracil-based therapy is determined by tumor genotype; and (b) the 3R repeat is a direct negative determinant of outcome.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Uchida
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hayashi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kawakami
authors.forename: Sylke
authors.initials: S
authors.lastname: Schneider
authors.forename: Ji Min
authors.initials: JM
authors.lastname: Yochim
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Kuramochi
authors.forename: Ken
authors.initials: K
authors.lastname: Takasaki
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Danenberg
authors.forename: Peter V
authors.initials: PV
authors.lastname: Danenberg
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D002887:Chromosomes, Human, Pair 18; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004338:Drug Combinations; D004586:Electrophoresis; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011725:Pyridines / Q000627:therapeutic use; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D005641:Tegafur / Q000627:therapeutic use; D013940:Thymidylate Synthase / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D018076:DNA, Complementary; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D012313:RNA; D004247:DNA; D013940:Thymidylate Synthase