Individualized predictive signatures for 5‐fluorouracil‐based chemotherapy in right‐ and left‐sided colon cancer

5‐Fluorouracil (5‐FU)‐based adjuvant chemotherapy (ACT) is widely used for the treatment of colon cancer. Colon cancers with different primary tumor locations are clinically and molecularly distinct, implied through their response to 5‐FU‐based ACT. In this work, using 69 and 133 samples of patients with stage II‐III right‐sided and left‐sided colon cancer (RCC and LCC) treated with post‐surgery 5‐FU‐based ACT, we preselected gene pairs whose relative expression orderings were significantly correlated with the disease‐free survival of patients by univariate Cox proportional hazards model. Then, from the identified prognostic‐related gene pairs, a forward‐stepwise selection algorithm was formulated to search for an optimal subset of gene pairs that resulted in the highest concordance index, referred to as the gene pair signature (GPS). We identified prognostic signatures, 3‐GPS and 5‐GPS, for predicting response to 5‐FU‐based ACT of patients with RCC and LCC, respectively, which were validated in independent datasets of GSE14333 and GSE72970. With the aid of the signatures, the transcriptional and genomic characteristics between the predicted responders and non‐responders were explored. Notably, both in RCC and LCC, the predicted responders to 5‐FU‐based ACT were characterized by hypermutation, whereas the predicted non‐responders were characterized by frequent copy number alternations. Finally, in comparison with the established relative expression ordering‐based signature, which was developed without considering the differences between RCC and LCC, the newly proposed signatures had a better predictive performance. In conclusion, 3‐GPS or 5‐GPS can robustly predict response to 5‐FU‐based ACT for patients with RCC or LCC, respectively, in an individual level.