Abstract 5349: Research in correlation of ADAR and AIMP2 DX2 using pan-cancer analysis
Authors: Song Seulki , Kim Daeyoon , Kim Yoosik , Yoon Sung-Soo , Kim Sunghoon , Koh Youngil 
Published: August 2018

AIMP2 is an interacting multifunctional protein complex of aminoacyl transferRNA synthase (ARS), a protein synthetase that binds to tRNA by activating amino acids. AIMP2 plays an important role as a tumor-suppressor gene, forming a complex with p53 and exon 2 deficient AIMP2 generated by alternative splicing mechanism (AIMP2-DX2) promotes carcinogenesis and loses its important role as a signaling modulator. On the other hand, the ADAR gene is a dsRNA-specific binding protein that triggers adenosine-to-inosine editing according to the hydrolytic adenosine deaminase activity and play an important role maintaining normal splicing activity. We studied the association between ADAR activity and AIMP2-DX2 generation. We used International Cancer Genome Consortium (ICGC) genomic data of cancer patients for this analysis: COAD-US (n=44), LUAD-US (n=42), and LUSC-US(n=48). Tophat and Cufflinks were used to map the raw RNA sequencing data of three carcinomas to a human reference and analyze for alternative transcription and splicing. The clustering algorithms-based Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to find enrichment in pathway with lists of genes from each group. The difference in the genetic variation patterns between the two groups were determined using "deconstructSigs" package in R which best interprets the sample's mutational profile. In whole ICGC RNA sequencing data, the amount of AIMP2 DX2 negatively correlated with ADAR expression. Subgroup analysis was performed for lung cancer and colon cancer samples based on AIMP2 and AIMP2-DX2 expression levels. Inflection point of AIMP2-DX2 expression curve was used as a cut-off value, and this value divided samples into two groups (7 samples with high AIMP2-DX2 and 121 samples with low AIMP2-DX2). We could observe obvious contribution of downregulated ADAR in high AIMP2-DX2 samples. When we examined mutations enriched in each group and the mutational pattern differences, mutations of tumor-suppressor genes including TP53 (71.4%) and APC (57.1%) were enriched in group of high AIMP2-DX2. The oncogenic mutations of KRAS (42.9%) and PIK3CA (28.6%) were also enriched in AIMP2-DX2 high patient group. The mutations enriched in group of highly expressed AIMP2-DX2 were further analyzed by DAVID functional annotation analysis, and MAPK signaling pathway and BASE excision repair signaling was discovered. Furthermore, the difference in the genetic variation patterns between the two groups was inspected based on COSMIC database. Mutational signature 9 related to hyper-mutation in immunoglobulin was expressed higher in AIMP2-DX2 elevated samples. Signatures 17 and 18 were also expressed with DX2 high samples. We compared the mutational enrichment and mutational pattern differences between the two groups according to the expression of the ADAR gene and verified the effect of the relationship between ADAR gene and AIMP2 DX2 on cancer development.

Citation Format: Seulki Song, Daeyoon Kim, Yoosik Kim, Sung-Soo Yoon, Sunghoon Kim, Youngil Koh. Research in correlation of ADAR and AIMP2 DX2 using pan-cancer analysis [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 5349.