Abstract 1983: Altered regulation of CEBP transcription factor family in normal bronchial epithelial cells of subjects with lung cancer or COPD

Abstract

Abstract Background: Antioxidant (AO), DNA repair (DNAR), and cell cycle control (CCC) genes play a role in protecting normal bronchial epithelial cells (NBEC) from damage, and sub-optimal function is associated with risk for COPD and lung cancer. CEBP transcription factors regulate key AO and DNA repair genes in NBEC. In this study, we investigated the association between CEBP transcription factor function and regulation of these gene pathways in NBEC of cancer (CA) and non-cancer (NC) COPD subjects. Methods: NBEC samples were obtained by bronchoscopy from 66 CA cases and 60 matched NC controls, and 30 NC COPD and 30 NC non-COPD controls defined by spirometry (FEV1 <0.7, FEV1/FVC <80% expected). RNA was extracted and reverse transcribed into cDNA with M-MLV using oligo dT primer. A targeted competitive multiplex next generation sequencing method was used to quantify expression of CEBPA, CEBPG, CEBPD, and 30 AO, DNAR, and CCC target genes. We assessed difference in inter-gene correlation of log-transformed transcript abundance by Pearson, difference in correlation by Fisher Z-transformation, dispersion difference by F-test and difference in mean by t-test. Results: Among NC controls, CEBPG transcript abundance was highly correlated with CEBPA (r = 0.78) and NFE2L2 (r = 0.86) but correlation was significantly lower in cancer (r = 0.45, 0.52, respectively). Correspondingly, CEBPA and CEBPG expression was more disperse among NC compared to CA (p-value = 1.6E-04, 4.2E-12, respectively). Further, correlation with CEBPG and/or CEBPA was significantly lower in cancer compared to controls for 13 AO, DNAR, or CCC genes, and significantly higher for only 2 genes. Moreover, CEBPA, CEBPG, CCND2, KEAP1, MYC, NFE2L2, RB1, TP53, and TP73 mean expression was lower in cancer compared to control while BRCA1, GSTM1, and GSTP1 expression was higher (p-value <0.01). Among non-COPD NC controls, CEBPG was positively correlated with OGG1, CCND2 and ERCC5 and correlation with each gene was significantly lower among COPD NC subjects (p-value of Z-score <0.01). In contrast, CEBPD correlation with GSTM4, ERCC5 and EGFR changed from positive in COPD to negative in control (p-value of Z-score <0.01). Further, CEBPA expression was more disperse in COPD compared to non-COPD control (p-value = 0.04). Conclusion: CEBPG and CEBPA expression regulation was different in CA compared to NC, and CEBPG, CEBPA and CEBPD regulation was different in NC COPD compared with NC non-COPD subjects. We hypothesize that inherited variation in NBEC regulation of these CEBP transcription factors and respective AO, DNAR, and CCC pathway genes in CA and/or COPD contributes to genetic risk. Exploration of mechanisms for variation in regulation of these genes will be the focus of additional studies in NBEC samples from over 500 subjects at risk for development for lung cancer in effort develop tests that better determine the group at genetic risk for lung cancer. Citation Format: Jiyoun Yeo, Erin Crawford, Xiaolu Zhang, Albert Levin, James Willey. Altered regulation of CEBP transcription factor family in normal bronchial epithelial cells of subjects with lung cancer or COPD. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1983.