Abstract Background: More than 50% of patients with colorectal cancer (CRC) develop metastatic disease to liver, which ultimately results in death in more than two thirds of the cases. Hence, earlier detection, together with the identification of patients at high-risk for tumor recurrence could significantly improve patient outcomes. Current paradigm asserts that metastasis must at least in part be a reflection of mutational and transcriptional landscape present in the majority of cells which constitute the primary tumor mass. Among these genomic determinants, transcription factors (TFs) are of particular interest, as they regulate the expression of both protein coding and noncoding RNAs. Keeping this in mind, we undertook an effort to develop a TF-based gene expression signature in primary CRC tissues that can help identify patients with a metastatic disease. Method: A comprehensive list of TFs was established from key relevant databases including TFdb, FANTOM and TFCAT. An in-silico discovery for differentially expressed TFs was performed in multiple, publicly available datasets. The final TF signature was examined in two independent cohorts of CRC patients (N=104 and 151 respectively). Statistical analyses included area under the receiver operating curve (AUROC) estimates, univariate and multivariate logistic regression, and Kaplan Meier survival outcomes. Lastly, we analyzed associations between our selected TF and their binding to various superenhancer elements by analyzing a publicly available H3K27ac dataset on 21 colorectal cell lines. Result: We developed a panel of 14 differentially expressed TFs by analyzing primary CRCs with and without liver metastasis. The AUROC values for liver metastasis-positive cases were 0.79 and 0.86 in the training and validation cohorts, respectively. The AUROC values improved to 0.93 in both cohorts on combining the signature with lymph node metastasis (LNM) status and the CEA levels. This signature was also associated with worse overall survival in the training (H.R (95%C.I) = 4.8(2.1-11.2), p<0.001) and validation cohorts (H.R (95%C.I) 8.9(3.1-25.6), p<0.001). In-silico analyses for superenhancer binding motifs for these TFs indicated that there exists a co-occurrence between many of the motif pairs, and 7 motifs (EHF, KLF7, MECP2, PURA, RARB, TCF4 and ZNF354C) were significantly more enriched within the superenhancers. Conclusions: We present a TF gene expression signature that can identify liver metastasis and can predict poor survival by analyzing primary tumor tissues from CRC patients. Transcriptional cooperativity between 7 of these 14 TFs along with their enriched binding to key superenhancer elements underscores their functional role in metastasis. Citation Format: Roshni Roy, Jesper Grud Madsen, Yasuhide Yamada, Yoshinaga Okugawa, Yuji Toiyama, Susanne Mandrup, Ajay Goel. Development of a superenhancer element-associated transcription factor signature in primary tumors for the identification of liver metastasis in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2958.