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

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.背景 转移是癌症患者死亡的主要诱因。当前医学研究尤为关注可区分短期发生转移与长期无转移患者的预后因素。本研究旨在探究筛选出的遗传多态性位点能否基于转移发生时机与长期转移风险，对结直肠癌患者进行分层。 方法 本研究的患者队列共纳入402例I~III期结直肠癌患者，其肿瘤均为微卫星不稳定低水平（microsatellite instability-low, MSI-L）或微卫星稳定（microsatellite stable, MSS）型。我们针对26个多态性位点采用多变量混合治愈模型——该模型适配存在大量长期无转移患者的研究场景——开展分析。此外，通过时变受试者工作特征（receiver operator characteristic, ROC）曲线分析，评估纳入显著单核苷酸多态性（single nucleotide polymorphism, SNP）后模型判别准确率的变化情况。 结果 在校正了具有统计学意义的基线特征后，共有2个多态性位点与转移发生时间显著相关：XRCC3基因Thr241Met位点的TT、TC基因型（p=0.042），以及TYMS基因5'-UTR可变数目串联重复（variable number tandem repeat, VNTR）的3R/3R基因型（p=0.009），均与更短的转移发生时间相关。受试者工作特征曲线分析显示，在已纳入显著基线特征的模型中加入上述多态性位点后，模型的判别准确率略有提升。 结论 本研究结果表明，XRCC3 Thr241Met与TYMS 5'-UTR VNTR多态性位点与结直肠癌患者的转移发生时间相关，或在加速转移进程中发挥潜在生物学作用。若该关联得以重复验证，将有助于结直肠癌患者精准医学的发展。