Thymidylate synthase genotypes and tumour regression in stage II/III rectal cancer patients after neoadjuvant fluorouracil-based chemoradiation

PurposeAccording 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.Patients and methods40 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.ResultsTS polymorphisms (5′-28 bp 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 +6 bp/+6 bp genotype correlating with high TS mRNA expression. TS1494del6 polymorphism was significantly associated with TS mRNA expression. Patients with TS1494del6 −6 bp/−6 bp or −6 bp/+6 bp genotypes showed significantly lower mean TS mRNA expression with 0.55 (range:0.33;0.84) as compared to +6 bp homozygotes with a mean expression of 0.90 (range:0.20;1.91) (p = 0.025). Furthermore, all patients with TS 3′-UTR −6 bp/−6 bp or −6 bp/+6 bp genotype (11/11) were responders as compared to only 20/26 (77%) of patients with TS 3′-UTR +6 bp/+6 bp genotype (p = 0.082). TS 5′-polymorphisms were not associated with neither tumour regression nor gene expression.ConclusionOur 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.