title: Prognostic implications of thymidylate synthase gene polymorphisms in patients with advanced small bowel adenocarcinoma treated with first-line fluoropyrimidine-based chemotherapy.
abstract: Thymidylate synthase (TS) gene polymorphisms such as tandem repeat (TR) polymorphisms and single-nucleotide polymorphisms (SNPs) affect transcriptional efficiency of the TS gene and may be prognostic markers for fluoropyrimidine-based therapy in various gastrointestinal cancers. However, data for TS polymorphisms on clinical outcomes in advanced small bowel adenocarcinoma (SBA) are limited. We retrospectively enrolled 58 locally advanced/metastatic SBA patients treated with first-line fluoropyrimidine-based chemotherapy and analyzed the relationship between TS genotypes and clinical outcomes in 30 patients who were available for tumor tissue. Based on TR polymorphisms and a G>C SNP in the promoter region of the TS gene, 74% of patients had high TS expression genotypes (2R/3RG, 3RG/3RC, 3RG/3RG); the remainder had low TS expression genotypes (2R/2R, 2R/3RC, 3RC/3RC). After a median follow-up of 48.8 months, median progression-free survival (PFS) and overall survival (OS) in all patients were 6.0 and 11.3 months, respectively. However, patients with low TS expression genotypes had better median PFS (12.8 vs. 4.3 months, P=0.027) and OS (28.8 vs. 8.9 months, P=0.025) than those with high TS expression genotypes. In multivariate analysis, poor Eastern Cooperative Oncology Group performance status [hazard ratio (HR), 2.85; 95% CI, 1.02-7.93] and high TS expression genotypes (HR, 3.49; 95% CI, 1.13-10.78) were independent prognostic factors for worse OS. Therefore, TS genotypes, based on a G>C SNP in the TR sequence of the TS gene, may be a useful biomarker for predicting outcomes for fluoropyrimidine-based chemotherapy in patients with locally advanced/metastatic SBA.
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Yhim
authors.affiliation: Department of Internal Medicine, Chonnam National University Medical School, Jeollanam-do, Republic of Korea.
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea.
authors.forename: Sam Yong
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Eulji University Hospital, Daejeon, Republic of Korea.
authors.forename: In Sung
authors.initials: IS
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea.
authors.forename: Kyu Taek
authors.initials: KT
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
authors.forename: Won Sup
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Department of Medicine, Dankook University Hospital, Cheonan, Republic of Korea.
authors.forename: Soon Il
authors.initials: SI
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Moo Rim
authors.initials: MR
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Chosun University Hospital, Gwangju, Republic of Korea.
authors.forename: Sang-Gon
authors.initials: SG
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea.
authors.forename: Hye-Suk
authors.initials: HS
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea.
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Chonnam National University Medical School, Jeollanam-do, Republic of Korea.
authors.forename: Ik-Joo
authors.initials: IJ
authors.lastname: Chung
authors.affiliation: Department of Internal Medicine, Chonnam National University Medical School, Jeollanam-do, Republic of Korea.
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Shim
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Na-Ri
authors.initials: NR
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Eun-Kee
authors.initials: EK
authors.lastname: Song
authors.affiliation: Department of Nursing, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Chang-Yeol
authors.initials: CY
authors.lastname: Yim
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D004379:Duodenal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D020080:Tandem Repeat Sequences / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D013940:Thymidylate Synthase; D005472:Fluorouracil