Identification and Clinical Validation of a Novel 4 Gene-Signature with Prognostic Utility in Colorectal Cancer.

Pankaj Ahluwalia,Sadanand Fulzele,Kimya Jones,Ashis K Mondal,Saleh Heneidi,Vamsi Kota,Ravindra Kolhe,Gagandeep K Gahlay,Sudha Ananth,Amyn M Rojiani,Chance Bloomer

doi:10.3390/ijms20153818

Abstract

Colorectal cancer (CRC) is a high burden disease with several genes involved in tumor progression. The aim of the present study was to identify, generate and clinically validate a novel gene signature to improve prediction of overall survival (OS) to effectively manage colorectal cancer. We explored The Cancer Genome Atlas (TCGA), COAD and READ datasets (597 samples) from The Protein Atlas (TPA) database to extract a total of 595 candidate genes. In parallel, we identified 29 genes with perturbations in > 6 cancers which are also affected in CRC. These genes were entered in cBioportal to generate a 17 gene panel with highest perturbations. For clinical validation, this gene panel was tested on the FFPE tissues of colorectal cancer patients (88 patients) using Nanostring analysis. Using multivariate analysis, a high prognostic score (composite 4 gene signature—DPP7/2, YWHAB, MCM4 and FBXO46) was found to be a significant predictor of poor prognosis in CRC patients (HR: 3.42, 95% CI: 1.71–7.94, p < 0.001 *) along with stage (HR: 4.56, 95% CI: 1.35–19.15, p = 0.01 *). The Kaplan-Meier analysis also segregated patients on the basis of prognostic score (log-rank test, p = 0.001 *). The external validation using GEO dataset (GSE38832, 122 patients) corroborated the prognostic score (HR: 2.7, 95% CI: 1.99–3.73, p < 0.001 *). Additionally, higher score was able to differentiate stage II and III patients (130 patients) on the basis of OS (HR: 2.5, 95% CI: 1.78–3.63, p < 0.001 *). Overall, our results identify a novel 4 gene prognostic signature that has clinical utility in colorectal cancer.

Highlights

Colorectal cancer (CRC) affects nearly 1.4 million individuals every year, which makes up to 10% of the global burden of cancer [1]
To identify risk genes in CRC, 595 candidate genes were accessed through The Cancer Genome Atlas (TCGA) database through The Human Protein Atlas
Most altered gene expression was observed for 10 genes in COAD dataset with YWHAB exhibiting significant changes in 39.10% of CRC patients (Table S2)

Summary

Introduction

Colorectal cancer (CRC) affects nearly 1.4 million individuals every year, which makes up to 10% of the global burden of cancer [1]. Several recent studies have identified gene expression signatures in cancer that have prognostic utility [4,5,6]. A robust risk-gene signature is required to further assist clinicians to tailor personalized treatment for diversity of CRC patients. Over the past few years, several consortium efforts have yielded massive data on multiple types of cancers. Building on TCGA datasets, secondary databases like TPA and cBioportal can provide hundreds of potential prognostic genes. These genes need additional validation through independent studies and our study is one such effort

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