Ultraconserved elements (UCEs) are non-coding genomic sequences completely identical among human, mouse, and rat species and harbor critical biological functions. We hypothesized that single nucleotide polymorphisms (SNPs) within UCEs are associated with clinical outcomes in colorectal cancer (CRC) patients.
Patients and Methods
Forty-eight SNPs within UCEs were genotyped in 662 patients with stage I–III CRC. The associations between genotypes and recurrence and survival were analyzed in stage II or III patients receiving fluoropyrimidine-based adjuvant chemotherapy using a training and validation design. The training set contained 115 stage II and 170 stage III patients, and the validation set contained 88 stage II and 112 stage III patients, respectively.
Eight SNPs were associated with clinical outcomes stratified by disease stage. In particular, for stage II patients with at least one variant allele of rs7849, consistent association with increased recurrence risk was observed in the training set (HR: 2.39; 95%CI: 1.04–5.52), replication set (HR: 3.70; 95%CI: 1.42–9.64), and meta-analysis (HR: 2.89; 95%CI: 1.54–5.41). There were several other SNPs that were significant in training set, but not in the validation set. These include: rs2421099, rs16983007 and rs10211390 with recurrence, and rs6590611 with survival in stage II patients; and SNPs rs6124509 and rs11195893 with recurrence in stage III patients. In addition, we also observed significant cumulative effect of multiple risk genotypes and potential gene-gene interactions on recurrence risk.
This is the first study to evaluate the association between SNPs within UCEs and clinical outcome in CRC patients. Our results suggest that SNPs within UCEs may be valuable prognostic biomarkers for locally advanced CRC patients receiving 5FU-based chemotherapy.