XRCC3 Thr241Met and TYMS variable number tandem repeat polymorphisms are associated with time-to-metastasis in colorectal cancer

PLoS One. 2018 Feb 2;13(2):e0192316. doi: 10.1371/journal.pone.0192316. eCollection 2018.

Abstract

Background: Metastasis is a major cause of mortality in cancer. Identifying prognostic factors that distinguish patients who will experience metastasis in the short-term and those that will be free of metastasis in the long-term is of particular interest in current medical research. The objective of this study was to examine if select genetic polymorphisms can differentiate colorectal cancer patients based on timing and long-term risk of metastasis.

Methods: The patient cohort consisted of 402 stage I-III colorectal cancer patients with microsatellite instability (MSI)-low (MSI-L) or microsatellite stable (MSS) tumors. We applied multivariable mixture cure model, which is the proper model when there is a substantial group of patients who remain free of metastasis in the long-term, to 26 polymorphisms. Time-dependent receiver operator characteristic (ROC) curve analysis was performed to determine the change in discriminatory accuracy of the models when the significant SNPs were included.

Results: After adjusting for significant baseline characteristics, two polymorphisms were significantly associated with time-to-metastasis: TT and TC genotypes of the XRCC3 Thr241Met (p = 0.042) and the 3R/3R genotype of TYMS 5'-UTR variable number tandem repeat (VNTR) (p = 0.009) were associated with decreased time-to-metastasis. ROC curves showed that the discriminatory accuracy of the model is increased slightly when these polymorphisms were added to the significant baseline characteristics.

Conclusions: Our results indicate XRCC3 Thr241Met and TYMS 5'-UTR VNTR polymorphisms are associated with time-to-metastasis, and may have potential biological roles in expediting the metastatic process. Once replicated, these associations could contribute to the development of precision medicine for colorectal cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA-Binding Proteins / genetics*
  • Humans
  • Methionine / genetics*
  • Neoplasm Metastasis*
  • Polymorphism, Single Nucleotide
  • Threonine / genetics*
  • Thymidylate Synthase / genetics*

Substances

  • DNA-Binding Proteins
  • X-ray repair cross complementing protein 3
  • Threonine
  • Methionine
  • TYMS protein, human
  • Thymidylate Synthase

Grants and funding

This work was primarily funded by the Research and Development Corporation (RDC) of Newfoundland and Labrador (NL) [5404.1723.101] and the Faculty of Medicine of Memorial University of Newfoundland awarded to Y.E. Yilmaz. Other funds that supported the Newfoundland Colorectal Cancer Registry (NFCCR) and helped collect the data used in this study are: Medical Research fund at Faculty of Medicine of Memorial University—Cox Award 2010, Canadian Institute of Health Research (CIHR) fund for the Colorectal Cancer Interdisciplinary Health Research Team at the University of Toronto and Memorial University of Newfoundland, the National Cancer Institute of Canada [18223 and 18226] and the Atlantic Innovation Fund for the Interdisciplinary Research Team in Human Genetics. M.E. Penney is partly supported by a Translational and Personalized Medicine Initiative (TPMI)/NL SUPPORT fellowship. A.A. Negandhi was supported by a CIHR Interdisciplinary Health Research Team Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.