Cytidine deaminase activity of APOBEC3 enzyme family is one of the causes of DNA mutations in many cancers. Members of this family are also RNA editors, capable of converting cytidine (C) bases at specific positions of RNAs to uracil (U). The prevalence and significance of APOBEC3-mediated site-specific C>U RNA editing in cancer is unknown. To study this in non-small cell lung cancer (NSCLC), we examined 1009 primary NSCLC tumors of The Cancer Genome Atlas project for RNA editing at 5,208 sites of 3,630 gene transcripts that are known to undergo APOBEC3-mediated RNA editing. A bioinformatics pipeline was developed to determine editing levels at these sites using whole exome (DNA) and RNA sequencing data. Cox regression, Spearman, and Welch's t tests were respectively used for analysis of survival, correlation, and group comparison. RNA editing could be determined for only some (mean 35, SD 64) of the examined sites because of poor sequencing coverage. For 333 sites (313 transcripts), editing was determinable for ≥10 tumors, with editing occurring at the sites in 2%-92% of tumors (mean 23%, SD 20%). Editing was most prevalent for SLC37A2 (92% of tumors), SERPIN1A (92%), and HPS1 (88%) transcripts. There were 366 tumors with editing determinable for ≥10 sites and occurring at ≥1 site. Among these tumors, editing occurred at 0.1%-100% of sites (mean 20%, SD 27%) at a level of 1%-18% (mean 6%, SD 3%). We summarized the site-specific editing determinations into an editing score, and used this measurement for further analyses. Editing score was on average 3.7x higher in tumors compared to adjacent normal tissues (P = 0.01). Tumors of squamous histology had 3.6x higher editing than adenocarcinoma (P <0.01). Patients with a history of smoking had 2x higher editing score than never-smokers (P = 0.02). There was no association of editing with pathologic tumor stage, but increased editing was associated with improved disease progression-free interval (HR = 0.4, P = 0.01). Correlation of tumor APOBEC3 gene expression levels with editing (r = 0.53 for APOBEC3A, 0.2-0.4 for others) was better than with APOBEC-mediated mutation burden (r = 0.29 for APOBEC3A, 0.07-0.27 for others). In conclusion, APOBEC3-mediated C>U RNA editing is prevalent in non-small cell lung cancer tumors, and reflects APOBEC3 gene expression better than APOBEC-mediated mutation burden. Additional research is needed to identify if editing occurs in cancer cells or in stromal cells of tumors and how it affects genesis and progression of cancer.

Citation Format: Mariko Asaoka, Frank Zhang, Takashi Ishikawa, Kazuaki Takabe, Saikrishna Yendamuri, Santosh K. Patnaik. APOBEC3-mediated C-to-U RNA editing in non-small cell lung cancer tumors is increased in patients with smoking history and squamous tumor histology [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 2518.