The M10 group had a higher proportion of patients with stage M1a (intrathoracic metastasis alone) and exhibited lower levels of thymidylate synthase (TS) than the F10 group (median H-score 10.0% vs. 60.0%; P = 0.031).
RNA-seq profiling indicated repression of epithelial-to-mesenchymal transition (EMT) signature genes upon TS knockdown, and TS-deficient cells showed an increased ability to invade and metastasize in vivo, consistent with the occurrence of a partial EMT phenotype.
This potential path highlights the crucial role of BMP2, hsa-miR-24, AP2 and MYC as the up-stream regulators of the path and hsa-miR-215 and TYMS as potential indicator of chemotherapeutic benefit in STS metastasis.
These findings indicate a possible prognostic role of TYMS mRNA expression and highlight a cluster of genes associated with nodal metastases that warrant further investigation in a larger cohort of patients with colorectal cancer treated with 5-FU-based adjuvant chemotherapy.
Thymidylate synthase and microsatellite instability in colorectal cancer: implications for disease free survival, treatment response and survival with metastases.
In both men and women, individuals with variant TS alleles were at reduced risk of having an advanced stage tumor (metastatic disease: OR = 0.35, 95% CI: 0.2-0.6 vs. wildtype TSER and 3'-UTR).
Fresh-frozen samples of metastases were obtained from 58 previously untreated patients with ACRC. mRNA expression of TS and DPD was quantified using an RT-PCR assay.
Thymidylate synthase activity measured in metastases was a significant predictor of 5FU responsiveness and the addition of the 677C>T genotype improved model prediction.
Patients with metastasized disease who expressed high TS levels display a low probability of responding to fluoropyrimidine-based treatment and have a poorer survival rate.
Univariate Cox analyses demonstrated that TS activity in primary tumor (the greater the TS, the poorer the survival; P =.040), TS promoter polymorphism in primary tumor (risk of death of 2R/3R v 2R/2R, 2.68; P =.035), and p53 stop mutation in metastasis (risk of death of stop mutations v wild type, 3.14; P =.018) were the only significant biologic predictors of specific survival.
The discordant TS expression between primary and metastatic tumors is a critical factor that must be taken into account when TS is being used as a predictive biomarker for the antitumor effect of 5-FU-based chemotherapy.