RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy

Abstract

Five‐year overall survival of stage III colorectal cancer (CRC) patients treated with standard adjuvant chemotherapy (ACHT) is highly variable. Genomic biomarkers and/or transcriptomic profiles identified lack of adequate validation. Aim of our study was to identify and validate molecular biomarkers predictive of ACHT response in stage III CRC patients by a transcriptomic approach. From a series of CRC patients who received ACHT, two stage III extreme cohorts (unfavorable vs. favorable prognosis) were selected. RNA‐sequencing was performed from fresh frozen explants. Tumors were characterized for somatic mutations. Validation was performed in stage III CRC patients extracted from two GEO datasets. According to disease‐free survival (DFS), 108 differentially expressed genes (104/4 up/downregulated in the unfavorable prognosis group) were identified. Among 104 upregulated genes, 42 belonged to olfactory signaling pathways, 62 were classified as pseudogenes (n = 17), uncharacterized noncoding RNA (n = 10), immune response genes (n = 4), microRNA (n = 1), cancer‐related genes (n = 14) and cancer‐unrelated genes (n = 16). Three out of four down‐regulated genes were cancer‐related. Mutational status (i.e., RAS, BRAF, PIK3CA) did not differ among the cohorts. In the validation cohort, multivariate analysis showed high PNN and KCNQ1OT1 expression predictive of shorter DFS in ACHT treated patients (p = 0.018 and p = 0.014, respectively); no difference was observed in untreated patients. This is the first study that identifies by a transcriptomic approach and validates PNN and KCNQ1OT1 as molecular biomarkers predictive of chemotherapy response in stage III CRC patients. After a further validation in an independent cohort, PNN and KCNQ1OT1 evaluation could be proposed to prospectively identify stage III CRC patients benefiting from ACHT.

Long Noncoding RNA KCNQ1OT1 is a Prognostic Biomarker and mediates CD8+ T cell exhaustion by regulating CD155 Expression in Colorectal Cancer

“…Although our sensitivity analysis revealed that the results only (Sun et al 2017) impacted the outcomes, the overall heterogeneity was low in our included studies. These results are consistent with the findings of previous studies [12]. Indeed, there are several limitations to this study that should be pointed out.…”

“…Recent studies have indicated that lncRNA KCNQ1OT1 participates in various biological processes, such as cell proliferation, apoptosis, and drug resistance [7][8][9]. In addition, lncRNA KCNQ1OT1 is involved in the progression of different cancers, including breast carcinoma [10], CRC [8,11,12], tongue carcinoma [13], lung carcinoma [14], and stomach carcinoma [15]. The clinicopathological characteristics, including overall survival, lymphatic meta-stasis, TNM stage, and tumor size, are also positively correlated with lncRNA KCNQ1OT1 expression levels in cancers [16][17][18][19].…”

Identification of a Six-Gene Signature Predicting Overall Survival for Oxaliplatin and 5-Fluorouracil Resistant Colon Cancer and Potential Drug-Repurposing

“…Such as, knockdown ANO1 expression could increase the apoptosis effects induced by L-OHP and 5-FU [26]. Moreover, RNA sequencing revealed PNN could be a predictive biomarker of clinical outcome in stage colorectal cancer patients treated with L-OHP and 5-Fu chemotherapy [27]. Additionally, it was reported that LEF1 was associated with 5-FU [28] and L-OHP caused bending of DNA produced targets for LEF1-binding [29].…”

Over-expression of RALYL suppresses the progression of ovarian clear cell carcinoma through inhibiting MAPK and CDH1 signaling pathways

“…By specific binding with RALY, RALYL could inhibit the oncogenic effects of RALY. Furthermore, HNRNPC, CRNKL1, PNN and PPIE were also reported to have a high expression and biological function in several cancers including ovarian cancer [21][22][23][24]. RALYL might also play the anti-tumor effects by suppressing these oncogenic genes.…”