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.
Colorectal cancer has emerged as a third most commonly diagnosed cancer in males and second in females. There is need for new tools in the form of prognostic biomarkers which could assist in tailoring of individualized treatment. Indoleamine 2,3-dioxygenase (IDO), a single chain oxido-reductase that serves as a catalyst for the degradation of tryptophan into kynurenine, has merged as a key player in T-cell suppression and in the induction of immune tolerance to tumors. IDO inhibitors have entered the clinical arena with a promise to restore immune functions in breast cancer patients. We identified through extensive literature search a list of IDO1-responsive genes. These gene along with IDO1 interferes with cancer control pathways and leads to cancer progression. The expression of following genes was quantified on Nanostring platform - IDO1, CTLA4, IL4R, PDL1, CTLA4, IL4R, HIF and IL6. Under an approved IRB protocol we identified 750 colon cancer patients at the Georgia Cancer Center with a 5 year follow-up. These patients were then divided into different experimental groups based on tumor stage (AJCC stages 1-4), survival (more or less than 3 years), tumor grade (AJCC grades 1-3), and age (older or younger than 68). A total of 88 patients fitted in our inclusion criteria on the basis of survival duration after diagnosis. The FFPE blocks were acquired from Medical College of Georgia, Augusta. Total RNA was isolated and quantified through Nanodrop method. The statistical analysis of data was performed using student t-test and Pearson correlation. IDO1 had significantly expressed at higher levels in stage IV patients (p = 0.01*). CTLA4 and IL4R were significantly expressed in stage IV patients with higher survival (p = 0.03*) and (p = 0.04*) respectively. PDL1 expression was higher in stage III patients with higher survival (p = 0.04*). CTLA4 was expressed at higher levels in patients with higher survival (>5 years). IDO1 was expressed at higher levels in males (p = 0.23*). In smokers, HIF and IL6 expression was higher as compared to non-smokers, (p = 0.02*). Preclinical data have shown that IDO1 inhibitors such as 1-Methyl-D-Tryptophan (1-MT) can synergize with chemotherapy in killing tumors. Therefore the inhibition of IDO as an approach to immunotherapy has a high amount of potential. Combining this new agent with current therapies may boost their efficacy and improve survival in TNBC patients. Furthermore, despite the rapid progress made in cancer immunotherapy, very few biomarkers are available for predicting the responsiveness and effectiveness of immunotherapy agents. Therefore, there is an urgent need to identify and develop such predictive biomarkers. These findings points to the clinical significance of IDO responsive genes and tested its importance in a gene expression based prognostic biomarker panel in CRC patients. Citation Format: Ravindra Kolhe, Chance Bloomer, Pankaj Ahluwalia, Chetan Pundkar, Saleh Heneidi, Ashis Mondal. Investigating the Indoleamine 2,3-dioxygenase 1 (IDO1) responsive gene expression panel in predicting outcome in stage matched colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4061.
Colorectal cancer (CRC) has emerged as the third most commonly diagnosed cancer in males and second most common in females. Although surgery, chemotherapy, and emerging immunotherapies have reduced mortality rates, tools that can assist in tailoring individualized treatments are needed. MDSC are immune-suppressive cells that interfere with the functioning of T cells and immune-inflammatory pathways. An extensive literature search identified 8 MDSC-centric genes which were tested for their prognostic significance in CRC. These genes; CEBPB, IL10, NOS2, RORC, S100A8, SOCS1, SOCS3, and TGFB1, along with their expression in tumor microenvironments could give new insights when correlated with clinical-pathologic features of colon cancer patients. The aim of the study is to quantify MDSC gene signatures in colorectal cancer patients. Under an IRB approved protocol, a total of 750 colon cancer patients at the Medical College of Georgia with 5 years of follow-up were initially selected. A total of 88 patients fit in our inclusion criteria, on the basis of survival duration after diagnosis. The FFPE blocks were acquired and patients were stratified on the basis of overall survival in two groups, with higher (>5 years) and lower survival (<1 year), as well as AJCC staging (I to IV), grade, gender and age. Total RNA was isolated and quantified through Nanodrop method. The statistical analysis of data was performed using student t-test and Pearson correlation. SOCS1 (p = 0.00*) was expressed in higher levels in patients with high survival (>5 years). Patients with low expression of TGFB1 survived longer compared to high expression group (p = 0.02*). On race comparison, CEBPA (p = 0.01*) showed significant expression in Caucasian population while NOS2 (p = 0.01*) expressed at higher levels in African Americans. These findings points to the clinical significance of MDSC based genes and tested the utility of a MDSC-related gene expression based prognostic biomarker panel for CRC patients. Citation Format: Saleh G. Heneidi, Chance Bloomer, Pankaj Ahluwalia, Ashis Mondal, Ravindra Kolhe. Investigating myeloid-derived suppressor cells (MDSC) gene expression in predicting outcome in stage matched colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2775.
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