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. 2021 Mar:153:90-98.
doi: 10.1016/j.lungcan.2021.01.015. Epub 2021 Jan 14.

RNA splicing and aggregate gene expression differences in lung squamous cell carcinoma between patients of West African and European ancestry

April E Deveaux  1 , Tyler A Allen  2 , Muthana Al Abo  2 , Xiaodi Qin  3 , Dadong Zhang  3 , Brendon M Patierno  1 , Lin Gu  2 , Jhanelle E Gray  4 , Chad V Pecot  5 , Holly K Dressman  6 , Shannon J McCall  7 , Rick A Kittles  8 , Terry Hyslop  9 , Kouros Owzar  9 , Jeffrey Crawford  10 , Steven R Patierno  10 , Jeffrey M Clarke  10 , Jennifer A Freedman  11
Affiliations

RNA splicing and aggregate gene expression differences in lung squamous cell carcinoma between patients of West African and European ancestry

April E Deveaux et al. Lung Cancer. 2021 Mar.

Abstract

Objectives: Despite disparities in lung cancer incidence and mortality, the molecular landscape of lung cancer in patients of African ancestry remains underexplored, and race-related differences in RNA splicing remain unexplored.

Materials and methods: We identified differentially spliced genes (DSGs) and differentially expressed genes (DEGs) in biobanked lung squamous cell carcinoma (LUSC) between patients of West African and European ancestry, using ancestral genotyping and Affymetrix Clariom D array. DSGs and DEGs were validated independently using the National Cancer Institute Genomic Data Commons. Associated biological processes, overlapping canonical pathways, enriched gene sets, and cancer relevance were identified using Gene Ontology Consortium, Ingenuity Pathway Analysis, Gene Set Enrichment Analysis, and CancerMine, respectively. Association with LUSC survival was conducted using The Cancer Genome Atlas.

Results: 4,829 DSGs and 267 DEGs were identified, including novel targets in NSCLC as well as genes identified previously to have relevance to NSCLC. RNA splicing events within 3 DSGs as well as 1 DEG were validated in the independent cohort. 853 DSGs and 29 DEGs have been implicated as potential drivers, oncogenes and/or tumor suppressor genes. Biological processes enriched among DSGs and DEGs included metabolic process, biological regulation, and multicellular organismal process and, among DSGs, ion transport. Overlapping canonical pathways among DSGs included neuronal signaling pathways and, among DEGs, cell metabolism involving biosynthesis. Gene sets enriched among DSGs included KRAS Signaling, UV Response, E2 F Targets, Glycolysis, and Coagulation. 355 RNA splicing events within DSGs and 18 DEGs show potential association with LUSC patient survival.

Conclusion: These DSGs and DEGs, which show potential biological and clinical relevance, could have the ability to drive novel biomarker and therapeutic development to mitigate LUSC disparities.

Keywords: Aggregate gene expression; European ancestry; Lung squamous cell carcinoma; RNA splicing; West African ancestry.

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Conflict of interest statement

The authors declare no potential conflicts of interest.

Figures

Figure 1.
Figure 1.. Differentially spliced genes (DSGs) and differentially expressed genes (DEGs) in lung squamous cell carcinoma (LUSC) between patients of West African (WestAfr) and European (Euro) ancestry.
Venn diagram depicting the number of genes exhibiting differential RNA splicing, differential aggregate gene expression, and both differential RNA splicing and differential aggregate gene expression in LUSC between patients of West Afr and Euro ancestry, as determined by transcriptome array analysis. The top 10 genes exhibiting differential RNA splicing, differential aggregate gene expression, or both differential RNA splicing and differential aggregate gene expression ranked by p-values are highlighted.
Figure 2.
Figure 2.. Biological processes enriched and overlapping canonical pathways among differentially spliced genes (DSGs) and differentially expressed genes (DEGs) in lung squamous cell carcinoma (LUSC) from patients of West African (WestAfr) and European (Euro) ancestry.
A. Biological processes enriched among DSGs from GO PANTHER. B. Overlapping canonical pathways among DSGs from Ingenuity Pathway Analysis. C. Biological processes enriched among all DEGs from GO PANTHER. D. Biological processes enriched among DEGs upregulated among patients of WestAfr ancestry from GO PANTHER. E. Biological processes enriched among DEGs downregulated among patients of WestAfr ancestry from GO PANTHER. F. Overlapping canonical pathways among all DEGs from Ingenuity Pathway Analysis. G. Gene sets enriched among DSGs from Gene Set Enrichment Analysis.
Figure 2.
Figure 2.. Biological processes enriched and overlapping canonical pathways among differentially spliced genes (DSGs) and differentially expressed genes (DEGs) in lung squamous cell carcinoma (LUSC) from patients of West African (WestAfr) and European (Euro) ancestry.
A. Biological processes enriched among DSGs from GO PANTHER. B. Overlapping canonical pathways among DSGs from Ingenuity Pathway Analysis. C. Biological processes enriched among all DEGs from GO PANTHER. D. Biological processes enriched among DEGs upregulated among patients of WestAfr ancestry from GO PANTHER. E. Biological processes enriched among DEGs downregulated among patients of WestAfr ancestry from GO PANTHER. F. Overlapping canonical pathways among all DEGs from Ingenuity Pathway Analysis. G. Gene sets enriched among DSGs from Gene Set Enrichment Analysis.
Figure 3.
Figure 3.. Association of differentially spliced genes (DSGs) and differentially expressed genes (DEGs) in lung squamous cell carcinoma (LUSC) from patients of West African (WestAfr) and European (Euro) ancestry with LUSC overall survival.
A. Kaplan-Meier plot showing Percent Spliced In (PSI) association with LUSC overall survival of (left) BCL2L1 Exon 2.1 as an alternative promoter and (right) FOXP3 exon 4 as a cassette exon. B. Kaplan-Meier plot showing gene expression association with LUSC overall survival in (left) TAT and (right) PRL.
See this image and copyright information in PMC

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