Global gene expression profile reveals a distinct transcriptomic profile predictive of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy

5-year overall survival of stage III colorectal cancer (CRC) patients ( pts) treated with standard adjuvant chemotherapy (CHT) (fluoropyrimidine-FP with/ without oxaliplatin-OHP) is still unsatisfactory and highly variable (42-88%). Although single molecular biomarkers and molecular signatures predictive of adjuvant CHT outcome have been identified in CRC, none of them has been validated.We hypothesized that differences in gene expression may be responsible for the variability of prognosis of stage III CRC pts. The goal of this study was to identify molecular biomarkers predictive of response to FP-based adjuvant CHT in stage III CRC pts. Materials and methods: From a large case series of CRC pts who received standard adjuvant CHT (5-fluorouracil/capecitabine +/- OHP) we selected two groups with favorable (no evidence of disease recurrence within 5 yrs from CHT, n = 12) or unfavorable (evidence of disease recurrence within 3 yrs from CHT, n = 12) prognosis. We analyzed 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 by statistical analysis. Results: Bioinformatic analysis identified 108 differentially expressed genes between the two groups (p value <0.01, False Discovery Rate <0.01): 104 genes were upregulated and 4 downregulated in the unfavorable compared with favorable prognosis groups. Magnitude of fold changes was within -2.5 to +3.5. Among these, 42 genes belonging to the olfactory pathways, were not considered. Among 66 remaining genes, 19 were pseudogenes, 7 uncharacterized non-coding RNA, 4 were involved in the immune response (e.g. IFNs) and one was a miRNA (MIR548I1). All these genes were upregulated. Further 9 genes were cancer-related (6 upregulated (e.g. CETN1 involved in cell adhesion) and 3 downregulated (e.g. ROR2 involved in Wnt pathway). The remaining genes (n = 26), most of which involved in key cellular processes (e.g. RNA processing: UPF3A upregulated; apoptosis: TMEM150B downregulated) have not yet been associated with cancer and/or cancer prognosis. Differentially expressed genes will be validated by RT-PCR. Conclusions: Stage III CRC pts with favorable and unfavorable prognosis following adjuvant CHT differs at a transcriptomic level. These findings, may have important implications for FP-based adjuvant CHT. Supported by Istituto Toscano Tumori and Ente Cassa Risparmio di Firenze.