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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  GSE 14333 and  GSE 72970. 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.

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