Abstract
BackgroundMetastasis 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.MethodsThe 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.ResultsAfter 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.ConclusionsOur 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.
Highlights
Colorectal cancer is a worldwide health concern, especially in developed regions [1]
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
receiver operator characteristic (ROC) curves showed that the discriminatory accuracy of the model is increased slightly when these polymorphisms were added to the significant baseline characteristics
Summary
Colorectal cancer is a worldwide health concern, especially in developed regions [1]. When the population is a combination of such patients, an advanced statistical approach known as the mixture cure model is appropriate in modeling time to metastasis While rarely used, this model can provide novel insight into cancer prognosis [7,8,9]. Patients with MSI-L or MSS tumor phenotypes are a mixture of two subgroups: patients who are the long-term metastasis-free survivors and patients susceptible to metastasis This suggests the existence of other factors that can influence the long-term risk and timing of metastasis in patients with the MSI-L/MSS subtype of colorectal cancer. To identify such factors, we applied the mixture cure model to 26 genetic polymorphisms in 402 colorectal cancer patients with the MSI-L/MSS tumor phenotype. 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
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