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©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jul 15, 2019; 11(7): 551-566
Published online Jul 15, 2019. doi: 10.4251/wjgo.v11.i7.551
TYMS/KRAS/BRAF molecular profiling predicts survival following adjuvant chemotherapy in colorectal cancer
Anastasios Ntavatzikos, Aris Spathis, Paul Patapis, Nikolaos Machairas, Georgia Vourli, George Peros, Iordanis Papadopoulos, Ioannis Panayiotides, Anna Koumarianou
Anastasios Ntavatzikos, Anna Koumarianou, Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Athens 12462, Greece
Aris Spathis, Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, “ATTIKON” University Hospital, Athens 12462, Greece
Paul Patapis, Nikolaos Machairas, 3rd Department of Surgery, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Athens 12462, Greece
Georgia Vourli, Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
George Peros, Iordanis Papadopoulos, Department of Surgery, Medical School, National and Kapodistrian University of Athens, Evgenideio Therapeutirio S.A., “I AGIA TRIAS”, Athens 11528, Greece
Ioannis Panayiotides, 2nd Department of Pathology, University of Athens, Medical School, “ATTIKON” University Hospital, Athens 12462, Greece
Author contributions: Ntavatzikos A, Spathis A, Panayiotides I and Koumarianou A designed the research; Ntavatzikos A, Patapis P, Spathis A and Koumarianou A collected the data; Ntavatzikos A, Spathis A and Panayiotides I performed the research; Ntavatzikos A, Patapis P, Spathis A and Koumarianou A analyzed the data; Ntavatzikos A and Koumarianou A wrote the paper; Panayiotides I and Papadopoulos I offered the technical or material supports; Ntavatzikos A, Spathis A and Koumarianou A drafted the manuscript; all authors critically revised the manuscript for important intellectual content.
Supported by Kapodistrias, National and Kapodistrian University of Athens, No. 70/3/8006 (Pythagoras II, EPEAEK II, GSRT) and No. 70/3/9114; Spathis A was supported during data collection from No. 70/3/8462 [PENED - European Social Fund (75%) and the Greek Ministry of Development-GSRT (25%)].
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board and Ethical Committee of University General Hospital Attikon, Athens, Greece.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: All authors declare no conflicts-of-interest related to this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Anastasios Ntavatzikos, MD, Research Scientist, Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Rimini 1, Haidari, Athens 12462, Greece. dmaal2@yahoo.gr
Telephone: +30-210-5831687 Fax: +30-210-5326446
Received: March 14, 2019
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
ARTICLE HIGHLIGHTS
Research background
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
Research motivation
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.
Research objectives
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.
Research methods
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
Research results
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.
Research conclusions
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.
Research perspectives
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.
