A 12‐gene signature to distinguish colon cancer patients with better clinical outcome following treatment with 5‐fluorouracil or FOLFIRI

Abstract

Currently, there is no marker in use in the clinical management of colon cancer to predict which patients will respond efficiently to 5‐fluorouracil (5‐FU), a common component of all cytotoxic therapies. Our aim was to develop and validate a multigene signature associated with clinical outcome from 5‐FU therapy and to determine if it could be used to identify patients who might respond better to alternate treatments. Using a panel of 5‐FU resistant and sensitive colon cancer cell lines, we identified 103 differentially expressed genes providing us with a 5‐FU response signature. We refined this signature using a clinically relevant DNA microarray‐based dataset of 359 formalin‐fixed and paraffin‐embedded (FFPE) colon cancer samples. We then validated the final signature in an external independent DNA microarray‐based dataset of 316 stage III FFPE samples from the PETACC‐3 (Pan‐European Trails in Alimentary Tract Cancers) clinical trial. Finally, using a drug sensitivity database of 658 cell lines, we generated a list of drugs that could sensitize 5‐FU resistant patients using our signature. We confirmed using the PETACC‐3 dataset that the overall survival of subjects responding well to 5‐FU did not improve with the addition of irinotecan (FOLFIRI; two‐sided log‐rank test p = 0.795). Conversely, patients who responded poorly to 5‐FU based on our 12‐gene signature were associated with better survival on FOLFIRI therapy (one‐sided log‐rank test p = 0.039). This new multigene signature is readily applicable to FFPE samples and provides a new tool to help manage treatment in stage III colon cancer. It also provides the first evidence that a subgroup of colon cancer patients can respond better to FOLFIRI than 5‐FU treatment alone.

Comparison of multiple transcriptomes exposes unified and divergent features of quiescent and activated skeletal muscle stem cells

“…Indeed, the last decades have witnessed many efforts to analyze microarray data to provide relevant gene signatures. In cancer biology, for example, gene markers were sought either for prognosis, i.e., lists of genes able to predict clinical outcome [ 45 ] or for molecular subtyping, i.e., list of genes able to classify different subtypes of a disease [ 46 , 47 ]. However, even if markers performed well, gene signatures derived from studies on the same treatments and diseases often resulted in gene lists with little overlap [ 48 ].…”

Transcriptome and long noncoding RNA sequencing of three extracellular vesicle subtypes released from the human colon cancer LIM1863 cell line

“…Abundant antisense lncRNAs selectively enriched in both exosome subtypes include RP5-940J5.9, RP11-290D2.6, as well as 7 ZFAS1 (ZNFX1 antisense RNA 1) and 5 C17orf76-AS1 (FAM211A antisense RNA 1) isoforms. Interestingly, C17orf76-AS1 (LRRC75 antisense RNA1) is up-regulated in 5-fluorocil resistant CRC cell lines and is reported to regulate apoptosis54. We found several highly-enriched antisense lncRNAs (Log2FC > 2) common to all three EV subtypes (e.g., ZFAS1).…”

Adjuvant Chemotherapy of Locally Advanced Colon Cancer: Final Results of a Randomized Trial Comparing 5-Fluorouracil and Folinic Acid with Folfiri

“…This might also be the reason why no association has been described between tumor location and outcome in older adjuvant trials. The observation that left-sided tumors display a more favorable prognosis than right-sided tumors is meanwhile a well-established fact and attributable to the exact documentation of tumor location within the colon allowing analysis [27,28]. It was also reported for the data sets of adjuvant trials comparing FUFA with Folfiri [11,12,29].…”

“…Therefore, in general, Folfiri cannot be recommended for adjuvant chemotherapy of locally advanced CC. Future trials should aim to identify tumor subtypes according to clinical and pathological parameters as well as their molecular profile [27,28,30,31,32], opening the chance to further individualize adjuvant treatment.…”