Abstract 3584: CENPA, MYBL2, and FOXM1 are identified as key transcriptional regulators in lung adenocarcinoma using TENET 2.0

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-08, Vol.80 (16_Supplement), p.3584-3584
• Main Authors: Mullen, Daniel J., Yan, Chunli, Kang, Diane S., Zhou, Beiyun, Borok, Zea, Marconett, Crystal N., Farnham, Peggy J., Offringa, Ite A., Rhie, Suhn K.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2020-3584

Lung cancer is the leading cause of cancer-related death in the United States, with lung adenocarcinoma being the most common subtype. Although a number of genetic alterations have been identified as potential drivers in lung adenocarcinoma, there is still a large gap in our understanding of tumor development. Epigenetic alterations have been implicated in the pathogenesis of tumors. To identify epigenetic alterations that drive lung adenocarcinoma, we used an improved version of the Tracing Enhancer Networks using Epigenetic Traits method (TENET 2.0) in primary normal lung and lung adenocarcinoma cells. We identified over 17,000 enhancers that appear activated in lung adenocarcinoma but not in normal lung and linked the activity of these enhancers to transcriptional regulators. We identified that CENPA, MYBL2, and FOXM1 are key transcriptional regulators activated in a subgroup of lung adenocarcinomas and they are linked to numerous cancer-specific enhancers. High expression of these regulators is associated with poor patient survival. In addition, we identified individual enhancers that are linked to these regulators and whose increased activities are strongly associated with poor patient survival. Knockdown experiments of MYBL2 and FOXM1 suggested that they regulate genes involved in controlling cell cycle progression and cell division. We also showed that high expression of TK1, a presumed target gene of a MYBL2-linked enhancer, is strongly associated with poor patient survival. Identification and characterization of key transcriptional regulators and associated cancer-specific enhancers in lung adenocarcinoma provides important insights into the deregulation of lung adenocarcinoma transcriptomes and novel potential targets for clinical intervention. Citation Format: Daniel J. Mullen, Chunli Yan, Diane S. Kang, Beiyun Zhou, Zea Borok, Crystal N. Marconett, Peggy J. Farnham, Ite A. Offringa, Suhn K. Rhie. CENPA, MYBL2, and FOXM1 are identified as key transcriptional regulators in lung adenocarcinoma using TENET 2.0 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3584.