Published online Jul 15, 2019. doi: 10.4251/wjgo.v11.i7.551
Peer-review started: March 15, 2019
First decision: April 16, 2019
Revised: April 30, 2019
Accepted: June 12, 2019
Article in press: June 13, 2019
Published online: July 15, 2019
Processing time: 125 Days and 0.2 Hours
A large proportion of patients with colorectal cancer (CRC) do not benefit from fluoro-pyrimidine-based adjuvant chemotherapy (FBAC). Fluoropyrimidines are thymidylate synthase (TYMS) inhibitors. Single nucleotide polymorphism (SNP) and various polymorphisms have been discovered in the 5’ untranslated region (UTR) and in the 3’UTR of the TYMS gene and their association with the survival of CRC patients is under consideration but with conflicting results. Molecular profiling could help clinicians to identify patients with CRC who may benefit from adjuvant chemotherapy, as shown by the associations of BRAF mutations with inferior survival in CRC patients after adjuvant chemotherapy. Also, although KRAS mutations have been found to be associated with poor patient survival, their role in the adjuvant setting is under investigation
There is a need to study the association of the numerous combinations of TYMS polymorphisms (3’UTR, 5’UTR and SNP) with CRC patient survival in a multivariate model including clinicopathological patients’ features and KRAS/BRAF mutations. The loss of heterozygosity (LOH) affects polymorphisms and should be included in such a study.
This study aimed to investigate the association of all known TYMS gene polymorphisms, LOH, KRAS and BRAF mutations with the survival of CRC patients treated with adjuvant chemotherapy.
Formalin-fixed paraffin-embedded tissues of 130 consecutive patients treated with FBAC were analysed for the detection of TYMS polymorphisms, mKRAS and mBRAF. Patients were classified according to 5’UTR TYMS polymorphisms and the predicted expression profile, into three groups (high, medium and low expression), utilizing the current literature. This categorization could reduce classification errors. Based on the presence or absence of the 3’UTR polymorphism ins/LOH patients were allocated into two groups (high and low risk of relapse), utilizing the results from univariate analysis of the 3’UTR TYMS polymorphisms. Cox regression models examined the associated 5-year survival outcomes
In this study, where BRAF, TYMS polymorphisms including SNP G>C and LOH were taken into consideration, both 3’UTR and 5’UTR polymorphisms emerged as independent prognostic factors of survival outcome after adjuvant chemotherapy for CRC. More specifically, the group of patients with tumors bearing 5’UTR polymorphisms 2RG/3RG, 2RG/LOH and 3RC/LOH was associated with better survival. On the contrary, patients with ins/LOH polymorphism in the 3’UTR had worse survival outcome. Also, mBRAF was found to correlate independently with worse prognosis.
Knowledge of TYMS gene polymorphisms and BRAF status indicates prognosis and could aid clinicians to distinguish the group of patients in need for adjuvant chemotherapy.
The study of the effect on the survival of CRC patients of the numerous genotypes resulting from the combinations of the 3’UTR and 5’UTR polymorphisms, the SNP and LOH requires larger prospective studies. These studies could validate our findings. Also, they could facilitate the grouping of the TYMS polymorphisms in more than just two groups and thus reduce the classification errors.