Thymidylate synthase genotypes and tumour regression in stage II/III rectal cancer patients after neoadjuvant fluorouracil-based chemoradiation.
OBJECTIVE
According to the CAO-/ARO-/AIO-94 trial of the German Rectal Cancer Study Group, pre-operative 5-fluorouracil (5-FU)-based long-term chemoradiotherapy (CT/RT) is recommended for patients with rectal cancer UICC stage II/III. However, despite the local benefit of neoadjuvant treatment, the overall prognostic value remains uncertain in comparison to adjuvant CT/RT. We assessed the impact of standardized pre-operative CT/RT and intratumoural mRNA levels and polymorphisms of the TS gene on histopathological tumour regression.


METHODS
40 patients with rectal cancer UICC stage II/III, receiving pre-operative 5-FU-based CT/RT followed by standardized surgery, including total mesorectal excision, were investigated. TS gene expression and TS polymorphisms of surgical specimens were correlated with the grade of histopathological tumour regression (0-4). Patients achieved regression grades 2-4 were determined as responders.


RESULTS
TS polymorphisms (5'-28bp repeat+G/C SNP and TS1494del6) could be determined in 39/40 (97.5%) and in 38/40 (95%) patients, respectively. Quantification of TS mRNA expression was successful in 36/40 (90%) patients. There was a highly significant linkage disequilibrium between 5'- and 3'-TS polymorphisms (p=0.0013). Interestingly, the majority of patients (82.1%) with 5'-TS genotypes known to be associated with low mRNA expression (2R/2R, 2R/3RC, 3RC/3RC) also possessed the TS1494del6 +6bp/+6bp genotype correlating with high TS mRNA expression. TS1494del6 polymorphism was significantly associated with TS mRNA expression. Patients with TS1494del6 -6bp/-6bp or -6bp/+6bp genotypes showed significantly lower mean TS mRNA expression with 0.55 (range:0.33;0.84) as compared to +6bp homozygotes with a mean expression of 0.90 (range:0.20;1.91) (p=0.025). Furthermore, all patients with TS 3'-UTR -6bp/-6bp or -6bp/+6bp genotype (11/11) were responders as compared to only 20/26 (77%) of patients with TS 3'-UTR +6bp/+6bp genotype (p=0.082). TS 5'-polymorphisms were not associated with neither tumour regression nor gene expression.


CONCLUSIONS
Our data suggest that the TS1494del6 polymorphism may be an important predictor for histopathological tumour regression in UICC II/III rectal cancer patients receiving neoadjuvant 5-FU-based CT/RT.
Stoehlmacher
Jan
J
Department of Internal Medicine I, University Hospital Carl Gustav Carus Dresden, Haematology and Medical Oncology, Fetscherstr. 74, 01307 Dresden, Germany. jan.stoehlmacher@uniklinikum-dresden.de
Goekkurt
Eray
E
Mogck
Ulrike
U
Aust
Daniela E
DE
Kramer
Michael
M
Baretton
Gustavo B
GB
Liersch
Torsten
T
Ehninger
Gerhard
G
Jakob
Christiane
C
D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000532:radiotherapy*; D013940:Thymidylate Synthase / Q000235:genetics*; D016896:Treatment Outcome
D012333:RNA, Messenger; D013940:Thymidylate Synthase; D005472:Fluorouracil