Abstract 4907: Transcriptomic profiling identifies a novel mitochondrial gene expression signature that predicts recurrence in microsatellite stable stage II and III colorectal cancer
Authors: GHATAK SOUVIK , Kandimalla Raju , Banwait Jasjit K. , Uetake Hiroyuki , Balaguer Francesc , Bujanda Luis , Goel Ajay 
Published: August 2019

Purpose: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States. Current TNM (Tumor, Node, and Metastasis) classification approach is suboptimal in determining the prognosis of CRC patients. While there is a general consensus that stage II and III CRC patients with microsatellite instability (MSI) exhibit better outcomes, there is a lack of availability of biomarkers that can predict prognosis in microsatellite stable (MSS) patients. Given the emerging evidence that mitochondrial (mt) genomic instability is one of the hallmark features of cancer progression, herein, we systematically explored and established a novel mt-gene panel as a prognostic signature in CRC.

Experimental design: Three genome wide mRNA expression profiling datasets were analyzed for the biomarker discovery (GSE33113, n=65) and validation (GSE14333, n=196; TCGA, n=62) of a mt-gene expression signature that predicts recurrence in stage II/III MSS CRC patients. Subsequently, a 14-gene signature was established, and independently tested (n=257) and validated (n=212) in two clinical cohorts, using qRT-PCR assays. The uni- and multi-variate Cox proportional hazard (CoxPH) regression analyses were performed to evaluate the performance of the mt-gene signature individually, and in combination with various clinicopathological factors (e.g. TNM staging, lymphatic invasion, and tumor infiltration) for predicting recurrence free survival (RFS).

Results: The expression analysis of 568 mt-genes in CRC patients with and without recurrence, resulted in the identification of 32 significantly dysregulated genes (p&lt;0.05). The univariate CoxPH analysis yielded a 14-gene signature that accurately predicted recurrence in the discovery (AUC = 0.89), and two independent validation cohorts (AUC = 0.75 and 0.79, respectively). This 14-gene signature demonstrated significant associations with poor RFS in independent testing and clinical validation cohorts of CRC patients (AUC = 0.87 and 0.73, respectively). Univariate analysis revealed that in addition to the mt-gene signature, TNM-stage (p = 0.007) and lymphatic invasion (p = 0.0004) were significant predictors of RFS; while multivariate analyses demonstrated that our mt-gene signature was an independent predictor (HR = 2.71; P&lt;0.001) of tumor recurrence in stage II/III CRC patients. Intriguingly, a risk-stratification model comprising of the 14-gene signature together with TNM-stage and lymphatic invasion status achieved an even superior AUC of 0.89 and 0.78 in both clinical cohorts.

Conclusions: We have identified a novel, 14-gene signature as an independent predictor of tumor recurrence; which in combination with TNM-stage and lymphatic invasion, offers an easy-to-translate and facile assay for the personalized risk-assessment in stage II/III MSS-CRC patients.

Citation Format: SOUVIK GHATAK, Raju Kandimalla, Jasjit K. Banwait, Hiroyuki Uetake, Francesc Balaguer, Luis Bujanda, Ajay Goel. Transcriptomic profiling identifies a novel mitochondrial gene expression signature that predicts recurrence in microsatellite stable stage II and III colorectal cancer [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 4907.