Abstract 1584: Transcriptome analysis links immune genes allelic expression imbalances to lung cancer
Authors: Liu Yanhong , Tsavachidis Spiridon , Kheradmand Farrah , Spitz Margaret R. , Amos Chris 
Published: August 2019

Abstract
Background: Genome-wide association study (GWAS) have identified over 45 susceptibility loci for lung cancer; many studies including our own group, have focused on low-frequency and rare coding variants using fine mapping and exome sequencing. This strategy, however, has met with limited success as about 90% of GWAS hits are noncoding and act primarily through altering transcriptional regulation in an allele-specific manner. The RNA-Seq based allele-specific expression (ASE) analysis affords an innovative approach to study preferential expression of an allele in direct relationship to its genotype, providing information on cis-regulatory effects for the expression of putative genes. However currently, there are no lung cancer studies that have rigorously evaluated the ASE variation in lung tumor and adjacent tissues.
Methods: Leveraging The Cancer Genome Atlas (TCGA) resource, we performed transcriptomic-wide ASE analysis using existing RNA-Seq datasets of paired tumor and adjacent tissues from 54 lung adenocarcinoma patients. We first quantified the RNA read counts of Referent and Alternate alleles of heterozygous variants, then evaluated the allelic imbalance on a per-sample basis using Beta-binomial test, and explored the differential ASE between tumor and adjacent tissues using paired Wilcoxon test. Functional regulatory consequences were generated from Ensembl Variant Effect Predictor.
Results: We identified total 208 significant ASEs, including 35 tissue-specific (only in tumor or only in adjacent), 28 sharing, and 145 differential variants. Of the 208 candidates, 41 were from the human leukocyte antigen (HLA) locus (primary DQA2, DQB1, DRB1, H and J), 26 were from the immunoglobulin (IG) superfamily (primary IGH, IGL, IGK and F11R). About 80% candidates were noncoding (mostly in 5’ and 3’ untranslated regions) and with regulatory features (21 promoter, seven enhancer, seven open chromatin region, two induce nonsense-mediated mRNA decay, one CTCF-binding site, and one transcription factor binding site). Other top genes included MDM2, APOL1, and CTSB. Pathway analyses revealed 27 genes involved in immune response pathway, and 12 genes involved in HLA antigen processing and presentation pathway.
Conclusion: This study is the first transcriptomics ASE analysis in lung adenocarcinoma. The key somatic cis-regulatory ASE variants identified from this study, especially immunogenic allelic variations from HLA and IG genes, could be used for identifying high-risk individuals for targeted lung cancer checkpoint blockade and related immunotherapies.
Citation Format: Yanhong Liu, Spiridon Tsavachidis, Farrah Kheradmand, Margaret R. Spitz, Chris Amos. Transcriptome analysis links immune genes allelic expression imbalances to lung cancer [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 1584.