Background <p>A subset of uterine cervical cancers recurs locally after definitive radiotherapy, highlighting the need for establishing biomarkers to predict radioresistance for dose optimisation. However, low local recurrence rate constitutes a barrier to research progress. This study aimed at exploring candidate predictive biomarker of radioresistance of uterine cervical cancer by analyzing multiple omics layers using nested case-control approach.</p> Methods <p>A discovery cohort (<i>n</i> = 8) was created from a series of 192 patients (all with squamous cell carcinoma of the uterine cervix underwent definitive radiotherapy) by 1:1 random case-control matching on pelvic recurrence (PR) for RNA sequencing. A validation cohort (<i>n</i> = 54) was created from the same series by 1:2 propensity score matching on PR for panel-based DNA sequencing and pelvic recurrence-free survival (PRFS) analysis. by using the Kaplan–Meier method and cause-specific proportional hazards models.</p> Results <p>In the discovery cohort, Gene set enrichment analysis revealed that the genes targeted by <i>MYC</i> were upregulated in patients with PR. In the validation cohort, the prevalence of <i>MYC</i> amplification was significantly greater in patients with PR than in those without (72% vs. 36%, respectively). The 5-year PRFS of patients with <i>MYC</i> amplification was significantly worse than that of those without (47.4% vs. 80.6%, respectively). Multivariate analysis identified <i>MYC</i> amplification as the significant predictor of PR.</p> Conclusions <p>These data suggest that upregulation of MYC plays a role in radioresistance of uterine cervical cancer, making <i>MYC</i> amplification a potential predictive biomarker for radioresistance.</p>