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. 2019 Jul 10;14(7):e0219469.
doi: 10.1371/journal.pone.0219469. eCollection 2019.

High thymidylate synthase gene expression predicts poor outcome after resection of hepatocellular carcinoma

David B Donner  1   2 , Eric K Nakakura  1   2 , Alan P Venook  2   3 , Heinz-Josef Lenz  4 , Wu Zhang  4 , Jimee Hwang  2   5 , Emily K Bergsland  2   3 , Meng Hsun Lin  1   2 , Kan Toriguchi  1   2 , Ricardo J Antonia  1   2 , Robert S Warren  1   2
Affiliations

High thymidylate synthase gene expression predicts poor outcome after resection of hepatocellular carcinoma

David B Donner et al. PLoS One. .

Abstract

Introduction: Prognosis after resection of hepatocellular carcinoma (HCC) is highly variable. Compared to clinicopathologic factors, the use of molecular markers to predict outcome has not been well studied. We investigated the prognostic importance of thymidylate synthase (TS) gene expression and polymorphisms in patients after resection of HCC.

Methods: Patients who underwent complete resection of HCC for whom tissue was available were identified. TS gene expression level and polymorphisms were determined in HCC specimens. Prognostic factors were evaluated using Kaplan-Meier curves and Cox proportional hazard models.

Results: The study included 67 patients. In univariate analysis, variables that negatively influenced survival included TNM stage, microvascular invasion, and high TS expression. For the high TS expression group, median survival was 54 months and 5-year actuarial survival was 47%. For the low TS expression group, median survival was not reached and the 5-year actuarial survival was 91%. In multivariate analysis, only high TS expression remained an independent predictor of poor survival (HR = 10.77, 95% CI 1.36-84.91; P = 0.02). TS gene polymorphisms were not associated with TS expression or overall survival.

Conclusions: High TS expression predicts poor outcome after resection of HCC. Molecular markers might be robust predictors of patient outcome after resection of HCC.

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Conflict of interest statement

This study was approved and funded by the National Comprehensive Cancer Network (NCCN) and by the Littlefield Family Foundation. The funding agencies were not involved in the design of the study and collection, analysis and interpretation of data, and in writing the manuscript. Support was also received from Roche Laboratories, Inc. Support from this commercial funder does not alter our adherence to PLOS ONE policies on sharing data and materials. Support from the commercial funder had no effect relating to employment, consultancy, patents, products in development, or marketed products. The corresponding author also declares on behalf of all the authors that there are no individual competing interests that could be perceived as interfering with the full and objective presentation, peer review, editorial decision making, or publication of this article.

Figures

Fig 1
Fig 1. Kaplan Meier plot of patient survival.
A. High and low patient TS mRNA levels defined by Maxstat. B. Kaplan Meier plot of patient survival based on mRNA expression characterizes overall survival as a function of TS mRNA levels assayed by qRT-PCR and dichotomized by maximum rank statistics (cutpoint = 0.12), HCC Resection Patients (n = 43).
Fig 2
Fig 2
(A) Overall Survival by 5'UTR enhancer region polymorphisms, HCC Resection patients (n = 67) (B) Overall Survival as a function of TS 5'UTR G/C SNP genotypes HCC Resection Patients (n = 67) (C) Overall Survival as a function of TS 3'UTR genotypes HCC Resection Patients (n = 67) (D) Overall Survival by TS combined 5'UTR/ 3'UTR polymorphisms, HCC Resection Group (n = 67); Low 5'UTR = 2R/2R + 2R/3C + 3C/3C; Low 3'UTR = +6bp/-6bp + -6bp/-6bp; High 5'UTR = 3G/3G + 3G/3C + 2/3G; High 3'UTR = +6bp/+6bp.
See this image and copyright information in PMC

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