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

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.

A genome-wide association study identifies single nucleotide polymorphisms associated with time-to-metastasis in colorectal cancer

“…When analyzing metastasis as a clinical outcome in colorectal cancer, it is observed that not all patients in a population-based cohort experience the outcome despite potentially long follow-up times [3, 4]. Consequently, the long-term metastasis-free survival probability estimate for such a cohort plateaus at a non-zero value.…”

“…Consequently, the long-term metastasis-free survival probability estimate for such a cohort plateaus at a non-zero value. This indicates the study cohort consists of a mixture of long-term metastasis-free survivors as well as patients who are susceptible to metastasis within the follow-up time [3, 5–9]. Thus, there might be prognostic factors distinguishing long-term metastasis-free survivors from patients who are susceptible to metastasis as well as factors determining timing of metastasis in the susceptible group [5, 6, 10].…”

“…The MSI tumor phenotype is an example of such a prognostic factor, since colorectal cancer patients with stage I-III MSI-H tumors have a favorable prognosis with very low risk of experiencing metastasis [11, 12]. On the other hand, the patient subgroup with stage I-III MSI-L/MSS tumors is a mixture of colorectal cancer patients that are susceptible and non-susceptible to metastasis [3]. Thus, in this study, we focus our efforts on this patient subgroup to explain more of the variability in the long-term risk and timing of metastasis.…”

Genetic Polymorphisms of DNA Repair Pathways in Sporadic Colorectal Carcinogenesis

“…Genetic polymorphisms of MLH3 rs175057 as well as MSH2 rs3771273, rs10188090 and rs10191478 may predict prognosis in patients with locally advanced rectal cancer who received preoperative chemoradiotherapy 134. XRCC3 Thr241Met polymorphism was associated with time-to-metastasis of CRC135. The specific role of the summarized polymorphisms of our review in clinical application and underlying mechanisms required further studies to elucidate.…”

Screening and identification of key biomarkers in lung squamous cell carcinoma by bioinformatics analysis

“…Gene polymorphisms of TYMS have been reported to have potential in improving the diagnosis, prevention and treatment of breast cancer (46). Hence, several studies are now focusing on the association between gene polymorphic variations of TYMS with various types of cancer (47–49). BIRC5 was upregulated in 76% LUSC samples and the expression in LUSC tissues was significantly higher compared with that in non-cancerous tissues (50).…”