PNNandKCNQ1OT1Can Predict the Efficacy of Adjuvant Fluoropyrimidine-Based Chemotherapy in Colorectal Cancer Patients

Abstract

The benefit of adjuvant chemotherapy in early stages of colorectal cancer (CRC) is still disappointing and the prediction of treatment outcome quite difficult. Recently, through a transcriptomic approach, we evidenced a role of PNN and KCNQ1OT1 gene expression in predicting response to fluoropyrimidine-based adjuvant chemotherapy in stage III CRC patients. Thus, the aim of this study was to validate in an independent cohort of stage II-III CRC patients our previous findings. PNN and KCNQ1OT1 mRNA expression levels were evaluated in 74 formalin fixed paraffin-embedded tumor and matched normal mucosa samples obtained by stage II-III CRC patients treated with fluoropyrimidine-based adjuvant chemotherapy. PININ, the protein encoded by PNN, was immunohistochemically evaluated in 15 tumor and corresponding normal mucosa samples, selected on the basis of a low, medium or high mRNA expression tumor/mucosa ratio. PNN and KCNQ1OT1 mRNA mean expression levels were significantly higher in tumor compared with normal tissues. Patients with high PNN or KCNQ1OT1 tumor mRNA levels according to ROC-based cut-offs, showed a shorter disease-free survival (DFS) compared with patients with low tumor mRNA gene expression. Also, patients with tumor mRNA expression values of both genes below the identified cut-offs had significantly longer DFS compared with patients with the expression of one or both genes above the cut-offs. In a representative large cohort of stage II-III CRC untreated patients retrieved from GEO datasets, no difference in DFS was observed between patients with high and low PNN or KCNQ1OT1 gene expression levels. These data confirm our previous findings and underscore the relevance of PNN and KCNQ1OT1 expression in predicting DFS in early stages of CRC treated with fluoropyrimidine-based adjuvant chemotherapy. If further validated in a prospective case series, both biomarkers could beCopyright © 2020 Cognizant Communication CorporationEU-3350 Oncology Research E-pub 3used to identify patients who benefit from this treatment and to offer alternative chemotherapy regimens to potential unresponsive patients. In relation to the suggested biological role of PNN and KCNQ1OT1 in CRC, they might also be exploited as potential therapeutic targets.

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“…14 Furthermore, some studies showed that PNN might cause resistance to chemotherapy, such as paclitaxel in ovarian cancer and fluoropyrimidine in colon cancer. 24 Given the inconsistency in PNN expression and function in cancers reported by previous studies, we aimed to investigate the subcellular localization and expression of PNN in RCC samples in the present study. We showed markedly increased PNN expression in RCC samples compared with that in adjacent normal tissues.…”

The World of Pseudogenes: New Diagnostic and Therapeutic Targets in Cancers or Still Mystery Molecules?

“…In colon cancer tissues, DUXAP8, RP11-54H7.4, and RP11-138J23.1 show elevated expression in advanced tumor stages [49]. In colorectal cancer tissues, increased KCNQ1OT1 (as well as PNN) is associated with shorter DFS of individuals in stage III treated with 5-FU adjuvant therapy [50]. REG1CP, TPTE2P1, and DUXAP8 are upregulated in colorectal cancer patient samples and cell lines [51][52][53].…”

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“…The PNN approach is a common data mining method that has been adapted to solve many pattern identification and classification issues (Lapucci et al 2020a ). In the PNN, the process is managed by a multilayer network consisting of four layers: an input layer, pattern layer, sum layer, and output layer.…”