A transcriptomic profile predicts clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy

Background: 5-year overall survival of stage III colorectal cancer (CRC) patients (pts) treated with standard adjuvant (adjuv) chemotherapy (CHT) (a fluoropyrimidine, FP +/- oxaliplatin, OHP) is still unsatisfactory and highly variable (42-88%). Although in CRC single molecular biomarkers or molecular signatures predictive of adjuv CHT outcome have been identified, none of them has been validated. The goal of this study was to identify and validate molecular biomarkers predictive of response to FP-based adjuv CHT in stage III CRC pts. Methods: From a large case series of CRC pts who received adjuv CHT (a FP +/- OHP) we selected two groups with favorable (F) (no evidence of disease recurrence (DR) within 5 yrs from CHT, n = 12) or unfavorable (UNF) (evidence of DR within 3 yrs from CHT, n = 12) prognosis. We used fresh frozen CRC explants according to an IRB approved protocol. Global gene expression profile was performed by Ion Proton System. Differentially expressed genes between groups were identified and some of them, selected according to a preliminary candidature on the basis of literature data or their pathobiological role, were validated by RT-PCR. Results: Bioinformatic analysis identified 108 differentially expressed genes between groups (p value <0.01, False Discovery Rate <0.01): 104 were up and 4 downregulated in the UNF group compared with the F prognosis group (fold change magnitude: range -2.5 +3.5). 42 genes belonging to the olfactory pathways, were not considered. Among 66 remaining genes, 19 were pseudogenes, 7 uncharacterized non-coding RNA, 4 involved in the immune response and one was a miRNA (MIR548I1). All these genes were upregulated. Further 9 genes were cancer-related (6 up and 3 downregulated). The remaining genes (n = 26), most of which involved in key cellular processes, have not yet been associated with cancer and/or cancer prognosis. Differential expression of 14 out of 16 selected genes was validated, e.g. CETN1 and ROR2 involved in cell adhesion and in Wnt pathway, respectively). Conclusions: Stage III CRC pts with F and UF prognosis following adjuv CHT differs at a transcriptomic level. These findings may have important implications for FP-based adjuv CHT.